Several drugs that target the tumour suppressor p53 pathway are now in clinical trials.
Small-molecule drugs that inhibit the protein–protein interaction between p53 and the E3 ubiquitin protein ligase MDM2 have been developed by many academic and pharmaceutical groups; some can induce complete regressions in xenograft models of human cancer.
Stapled peptides are an alternative to classical small-molecule inhibitors; they are active in animal models of cancer as dual inhibitors of the p53–MDM2 and p53–MDM4 interactions.
The potential side effects of activating p53 in normal tissues are still being explored. So far, the major effect seems to be the induction of neutropenia.
The activation of p53 by the MDM2 inhibitors can induce growth arrest, senescence or apoptosis in tumour cells. Studies to understand this variation have identified expression levels of key components of both the intrinsic and extrinsic apoptotic machinery as key regulators. Drug combinations that target these apoptotic pathways may increase the efficacy of p53 therapy.
Drugs that reactivate the wild-type functions of mutant p53 are also in clinical trials, although their mechanism of action is still unclear.
Structural studies of mutant p53 are providing druggable sites on the surface of the protein to which small molecules can bind.
As well as inducing apoptotic death in cancer cells, the p53 pathway has a role in preventing the earliest development of cancer. This surveillance function of p53 is distinct and involves a discrete group of p53-induced genes that regulate DNA repair and metabolism, and does not require the genes encoding p53-upregulated modulator of apoptosis (PUMA), phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1; also known as NOXA) or cyclin-dependent kinase inhibitor 1A (CDKN1A).
The p53-inducing drugs may have a role in chemoprevention.
The tumour suppressor p53 is the most frequently mutated gene in human cancer, with more than half of all human tumours carrying mutations in this particular gene. Intense efforts to develop drugs that could activate or restore the p53 pathway have now reached clinical trials. The first clinical results with inhibitors of MDM2, a negative regulator of p53, have shown efficacy but hint at on-target toxicities. Here, we describe the current state of the development of p53 pathway modulators and new pathway targets that have emerged. The challenge of targeting protein–protein interactions and a fragile mutant transcription factor has stimulated many exciting new approaches to drug discovery.
Subscribe to Journal
Get full journal access for 1 year
only $22.08 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Lane, D. P. & Verma, C. Mdm2 in evolution. Genes Cancer 3, 320–324 (2012).
Hock, A. & Vousden, K. H. Regulation of the p53 pathway by ubiquitin and related proteins. Int. J. Biochem. Cell Biol. 42, 1618–1621 (2010).
Huang, L. et al. The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo. Proc. Natl Acad. Sci. USA 108, 12001–12006 (2011).
Vogelstein, B., Lane, D. & Levine, A. J. Surfing the p53 network. Nature 408, 307–310 (2000).
Vassilev, L. T. et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303, 844–848 (2004). This is the critical first paper describing a p53–MDM2 interaction inhibitor.
MacCallum, D. E. et al. The p53 response to ionising radiation in adult and developing murine tissues. Oncogene 13, 2575–2587 (1996).
Komarova, E. A. et al. Transgenic mice with p53-responsive lacZ: 53 activity varies dramatically during normal development and determines radiation and drug sensitivity in vivo. EMBO J. 16, 1391–1400 (1997).
Christophorou, M. A., Ringshausen, I., Finch, A. J., Swigart, L. B. & Evan, G. I. The pathological response to DNA damage does not contribute to p53-mediated tumour suppression. Nature 443, 214–217 (2006). This paper uses a toggled p53 genetic construct to show, for the first time, that that the p53-mediated DNA damage response can be separated from its tumour suppressor activity.
Ringshausen, I., O'Shea, C. C., Finch, A. J., Swigart, L. B. & Evan, G. I. Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo. Cancer Cell 10, 501–514 (2006).
Mendrysa, S. M. & Perry, M. E. Tumor suppression by p53 without accelerated aging: just enough of a good thing? Cell Cycle 5, 714–717 (2006).
Mendrysa, S. M. et al. Mdm2 is critical for inhibition of p53 during lymphopoiesis and the response to ionizing irradiation. Mol. Cell. Biol. 23, 462–472 (2003).
Bond, G. L. et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119, 591–602 (2004).
Garcia-Cao, I. et al. “Super p53” mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO J. 21, 6225–6235 (2002).
Efeyan, A., Garcia-Cao, I., Herranz, D., Velasco-Miguel, S. & Serrano, M. Tumour biology: policing of oncogene activity by p53. Nature 443, 159 (2006).
Martins, C. P., Brown-Swigart, L. & Evan, G. I. Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 127, 1323–1334 (2006).
Ventura, A. et al. Restoration of p53 function leads to tumour regression in vivo. Nature 445, 661–665 (2007).
Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007).
Li, T. et al. Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence. Cell 149, 1269–1283 (2012). This paper is one of three recently published studies that conclude — using an acetylation-defective mutant p53 — that p53-dependent tumour suppression can occur without inducing p21 cell cycle arrest or PUMA- and NOXA-driven apoptosis.
Brady, C. A. et al. Distinct p53 transcriptional programs dictate acute DNA-damage responses and tumor suppression. Cell 145, 571–583 (2011). This paper shows that a p53 mutant that is defective in either TAD1 or TAD2 is still able to suppress tumour development. The double TAD1/TAD2 mutant is inactive, which implies that some p53-dependent transcription is needed, but not of the commonly studied target genes CDKN1A, PUMA and NOXA.
Jiang, D. et al. Full p53 transcriptional activation potential is dispensable for tumor suppression in diverse lineages. Proc. Natl Acad. Sci. USA 108, 17123–17128 (2011).
Deng, C., Zhang, P., Harper, J. W., Elledge, S. J. & Leder, P. Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 82, 675–684 (1995).
Villunger, A. et al. p53- and drug-induced apoptotic responses mediated by BH3-only proteins Puma and Noxa. Science 302, 1036–1038 (2003).
Valente, L. J. et al. p53 efficiently suppresses tumor development in the complete absence of its cell-cycle inhibitory and proapoptotic effectors p21, Puma, and Noxa. Cell Rep. 3, 1339–1345 (2013). In this paper, p53 is shown to be able to block tumour development in mice that lack genes encoding p21, PUMA and NOXA.
Sablina, A. A. et al. The antioxidant function of the p53 tumor suppressor. Nature Med. 11, 1306–1313 (2005). This remarkable paper shows that treatment with the antioxidant compound N -acetylcysteine blocks tumour development in p53-null mice.
Robertson, K. D. & Jones, P. A. The human ARF cell cycle regulatory gene promoter is a CpG island which can be silenced by DNA methylation and down-regulated by wild-type p53. Mol. Cell. Biol. 18, 6457–6473 (1998).
Roxburgh, P. et al. Small molecules that bind the Mdm2 RING stabilize and activate p53. Carcinogenesis 33, 791–798 (2012).
Li, C. & Johnson, D. E. Liberation of functional p53 by proteasome inhibition in human papilloma virus-positive head and neck squamous cell carcinoma cells promotes apoptosis and cell cycle arrest. Cell Cycle 12, 923–934 (2013).
Kitagaki, J., Agama, K. K., Pommier, Y., Yang, Y. & Weissman, A. M. Targeting tumor cells expressing p53 with a water-soluble inhibitor of Hdm2. Mol. Cancer Ther. 7, 2445–2454 (2008).
Lain, S. et al. Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell 13, 454–463 (2008).
Brachmann, R. K., Yu, K., Eby, Y., Pavletich, N. P. & Boeke, J. D. Genetic selection of intragenic suppressor mutations that reverse the effect of common p53 cancer mutations. EMBO J. 17, 1847–1859 (1998).
Nikolova, P. V., Wong, K. B., DeDecker, B., Henckel, J. & Fersht, A. R. Mechanism of rescue of common p53 cancer mutations by second-site suppressor mutations. EMBO J. 19, 370–378 (2000).
Petitjean, A. et al. Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum. Mutat. 28, 622–629 (2007).
Brown, C. J., Lain, S., Verma, C. S., Fersht, A. R. & Lane, D. P. Awakening guardian angels: drugging the p53 pathway. Nature Rev. Cancer 9, 862–873 (2009).
Cheok, C. F., Verma, C. S., Baselga, J. & Lane, D. P. Translating p53 into the clinic. Nature Rev. Clin. Oncol. 8, 25–37 (2011).
Picksley, S. M., Vojtesek, B., Sparks, A. & Lane, D. P. Immunochemical analysis of the interaction of p53 with MDM2; fine mapping of the MDM2 binding site on p53 using synthetic peptides. Oncogene 9, 2523–2529 (1994).
Kussie, P. H. et al. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 274, 948–953 (1996).
Bottger, A. et al. Design of a synthetic Mdm2-binding mini protein that activates the p53 response in vivo. Curr. Biol. 7, 860–869 (1997).
Chene, P. et al. A small synthetic peptide, which inhibits the p53-hdm2 interaction, stimulates the p53 pathway in tumour cell lines. J. Mol. Biol. 299, 245–253 (2000).
Wang, S., Zhao, Y., Bernard, D., Aguilar, A. & Kumar, S. in Protein-Protein Interactions Vol. 8 (ed. Wendt, M. D.) 57–79 (Springer, 2012).
Grasberger, B. L. et al. Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells. J. Med. Chem. 48, 909–912 (2005).
Allen, J. G. et al. Discovery and optimization of chromenotriazolopyrimidines as potent inhibitors of the mouse double minute 2−tumor protein 53 protein−protein interaction. J. Med. Chem. 52, 7044–7053 (2009).
Orner, B. P., Ernst, J. T. & Hamilton, A. D. Toward proteomimetics: terphenyl derivatives as structural and functional mimics of extended regions of an α-helix. J. Am. Chem. Soc. 123, 5382–5383 (2001).
Yin, H. et al. Terphenyl-based helical mimetics that disrupt the p53/HDM2 interaction. Angew. Chem. Int. Ed. Engl. 44, 2704–2707 (2005).
Go, M. L., Wu, X. & Liu, X. L. Chalcones: an update on cytotoxic and chemoprotective properties. Curr. Med. Chem. 12, 483–499 (2005).
Stoll, R. et al. Chalcone derivatives antagonize interactions between the human oncoprotein MDM2 and p53. Biochemistry 40, 336–344 (2001).
Shangary, S. et al. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc. Natl Acad. Sci. USA 105, 3933–3938 (2008). This paper describes the second set of p53–MDM2 inhibitors, showing dramatic preclinical activity in mouse models.
Zhao, Y. et al. A potent small-molecule inhibitor of the MDM2–p53 interaction (MI-888) achieved complete and durable tumor regression in mice. J. Med. Chem. 56, 5553–5561 (2013).
Czarna, A. et al. Robust generation of lead compounds for protein–protein interactions by computational and MCR chemistry: 53/Hdm2 antagonists. Angew. Chem. Int. Ed. 49, 5352–5356 (2010).
Boettcher, A. et al. 3-imidazolyl-indoles for the treatment of proliferative diseases. WO Patent 2008119741 (2008).
Hardcastle, I. R. et al. Isoindolinone inhibitors of the murine double minute 2 (MDM2)-p53 protein-protein interaction: structure-activity studies leading to improved potency. J. Med. Chem. 54, 1233–1243 (2011).
Burdack, C. et al. HDM2 ligands. WO Patent 2010028862 (2010).
Essmann, F. & Schulze-Osthoff, K. Translational approaches targeting the p53 pathway for anti-cancer therapy. Br. J. Pharmacol. 165, 328–344 (2012).
Bogen, S. L. et al. Substituted piperidines that increase P53 activity and the uses thereof. WO Patent 2011046771A1 (2011).
Bertamino, A. et al. Synthesis, in vitro, and in cell studies of a new series of [indoline-3,2′-thiazolidine]-based p53 modulators. J. Med. Chem. 56, 5407–5421 (2013).
Galatin, P. S. & Abraham, D. J. A nonpeptidic sulfonamide inhibits the p53-mdm2 interaction and activates p53-dependent transcription in mdm2-overexpressing cells. J. Med. Chem. 47, 4163–4165 (2004).
Rew, Y. et al. Structure-based design of novel inhibitors of the MDM2–p53 interaction. J. Med. Chem. 55, 4936–4954 (2012).
Gonzalez-Lopez de Turiso, F. et al. Rational design and binding mode duality of MDM2–p53 inhibitors. J. Med. Chem. 56, 4053–4070 (2013).
Lucas, B. S. et al. An expeditious synthesis of the MDM2–p53 inhibitor AM-8553. J. Am. Chem. Soc. 134, 12855–12860 (2012).
Riedinger, C. et al. Understanding small-molecule binding to MDM2: insights into structural effects of isoindolinone inhibitors from NMR spectroscopy. Chem. Biol. Drug Design 77, 301–308 (2011).
Michelsen, K. et al. Ordering of the N-terminus of human MDM2 by small molecule inhibitors. J. Am. Chem. Soc. 134, 17059–17067 (2012).
Wei, S. J. et al. In vitro selection of mutant HDM2 resistant to Nutlin inhibition. PLoS ONE 8, e62564 (2013).
Vu, B. et al. Discovery of RG7112: a small-molecule MDM2 inhibitor in clinical development. ACS Med. Chem. Lett. 4, 466–469 (2013).
Ding, Q. et al. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J. Med. Chem. 56, 5979–5983 (2013).
Wade, M. & Wahl, G. M. Targeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry? Mol. Cancer Res. 7, 1–11 (2009).
Gembarska, A. et al. MDM4 is a key therapeutic target in cutaneous melanoma. Nature Med. 18, 1239–1247 (2012).
Lu, M. et al. Restoring p53 function in human melanoma cells by inhibiting MDM2 and cyclin B1/CDK1-phosphorylated nuclear iASPP. Cancer Cell 23, 618–633 (2013).
van Leeuwen, I. M. et al. Mechanism-specific signatures for small-molecule p53 activators. Cell Cycle 10, 1590–1598 (2011).
Leão, M. et al. Discovery of a new small-molecule inhibitor of p53–MDM2 interaction using a yeast-based approach. Biochem. Pharmacol. 85, 1234–1245 (2013).
Nakamura, Y. et al. Siladenoserinols A–L: new sulfonated serinol derivatives from a tunicate as inhibitors of p53–Hdm2 interaction. Org. Lett. 15, 322–325 (2012).
Reed, D. et al. Identification and characterization of the first small molecule inhibitor of MDMX. J. Biol. Chem. 285, 10786–10796 (2010).
Noguchi, T. et al. Affinity-based screening of MDM2/MDMX–p53 interaction inhibitors by chemical array: identification of novel peptidic inhibitors. Bioorg. Med. Chem. Lett. 23, 3802–3805 (2013).
Graves, B. et al. Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization. Proc. Natl Acad. Sci. USA 109, 11788–11793 (2012).
ElSawy, K. M. et al. On the interaction mechanisms of a p53 peptide and nutlin with the MDM2 and MDMX proteins: a Brownian dynamics study. Cell Cycle 12, 394–404 (2013).
Hernychova, L. et al. Identification of a second Nutlin-3 responsive interaction site in the N-terminal domain of MDM2 using hydrogen/deuterium exchange mass spectrometry. Proteomics 13, 2512–2525 (2013). This paper characterizes, for the first time, the relevance of a secondary interaction site for MDM2 inhibitors, thus possibly identifying a new druggable site.
Pazgier, M. et al. Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX. Proc. Natl Acad. Sci. USA 106, 4665–4670 (2009).
Phan, J. et al. Structure-based design of high affinity peptides inhibiting the interaction of p53 with MDM2 and MDMX. J. Biol. Chem. 285, 2174–2183 (2010).
Li, C. et al. Systematic mutational analysis of peptide inhibition of the p53-MDM2/MDMX interactions. J. Mol. Biol. 398, 200–213 (2010).
Liu, M. et al. D-peptide inhibitors of the p53-MDM2 interaction for targeted molecular therapy of malignant neoplasms. Proc. Natl Acad. Sci. USA 107, 14321–14326 (2010).
Dastidar, S. G., Lane, D. P. & Verma, C. S. Multiple peptide conformations give rise to similar binding affinities: molecular simulations of p53-MDM2. J. Am. Chem. Soc. 130, 13514–13515 (2008).
Brown, C. J. et al. C-terminal substitution of MDM2 interacting peptides modulates binding affinity by distinctive mechanisms. PLoS ONE 6, e24122 (2011).
Zhou, W. et al. Improved eIF4E binding peptides by phage display guided design: plasticity of interacting surfaces yield collective effects. PLoS ONE 7, e47235 (2012).
Schafmeister, C. E., Po, J. & Verdine, G. L. An all-hydrocarbon cross-linking system for enhancing the helicity and metabolic stability of peptides. J. Am. Chem. Soc. 122, 5891–5892 (2000).
Bernal, F., Tyler, A. F., Korsmeyer, S. J., Walensky, L. D. & Verdine, G. L. Reactivation of the p53 tumor suppressor pathway by a stapled p53 peptide. J. Am. Chem. Soc. 129, 2456–2457 (2007).
Bernal, F. et al. A stapled p53 helix overcomes HDMX-mediated suppression of p53. Cancer Cell 18, 411–422 (2010). This is the first description of stapled peptide inhibitors of the p53–MDM2interaction.
Brown, C. J. et al. Stapled peptides with improved potency and specificity that activate p53. ACS Chem. Biol. 8, 506–512 (2013). This paper describes new stapled peptides that have potent activity in the induction of p53 in cell-based reporter assays.
Chang, Y. S. et al. Stapled α-helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy. Proc. Natl Acad. Sci. USA 110, E3445–E3454 (2013). This paper describes a stapled peptide developed by Aileron Therapeutics that shows in vitro and in vivo efficacy.
Brown, Z. Z. et al. A spiroligomer alpha-helix mimic that binds HDM2, penetrates human cells and stabilizes HDM2 in cell culture. PLoS ONE 7, e45948 (2012).
Ji, Y. et al. In vivo activation of the p53 tumor suppressor pathway by an engineered cyclotide. J. Am. Chem. Soc. 135, 11623–11633 (2013).
Walensky, L. D. et al. Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 305, 1466–1470 (2004).
Walensky, L. D. et al. A stapled BID BH3 helix directly binds and activates BAX. Mol. Cell 24, 199–210 (2006).
Okamoto, T. et al. Stabilizing the pro-apoptotic BimBH3 helix (BimSAHB) does not necessarily enhance affinity or biological activity. ACS Chem. Biol. 8, 297–302 (2013).
Khoo, K. H., Andreeva, A. & Fersht, A. R. Adaptive evolution of p53 thermodynamic stability. J. Mol. Biol. 393, 161–175 (2009).
Joerger, A. C. & Fersht, A. R. Structural biology of the tumor suppressor p53. Annu. Rev. Biochem. 77, 557–582 (2008).
Sawkar, A. R. et al. Chemical chaperones increase the cellular activity of N370S beta-glucosidase: a therapeutic strategy for Gaucher disease. Proc. Natl Acad. Sci. USA 99, 15428–15433 (2002).
Sawkar, A. R. et al. Gaucher disease-associated glucocerebrosidases show mutation-dependent chemical chaperoning profiles. Chem. Biol. 12, 1235–1244 (2005).
Martinez Molina, D. et al. Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay. Science 341, 84–87 (2013).
Boeckler, F. M. et al. Targeted rescue of a destabilized mutant of p53 by an in silico screened drug. Proc. Natl Acad. Sci. USA 105, 10360–10365 (2008).
Wilcken, R. et al. Halogen-enriched fragment libraries as leads for drug rescue of mutant p53. J. Am. Chem. Soc. 134, 6810–6818 (2012).
Liu, X. et al. Small molecule induced reactivation of mutant p53 in cancer cells. Nucleic Acids Res. 41, 6034–6044 (2013).
Basse, N. et al. Toward the rational design of p53-stabilizing drugs: probing the surface of the oncogenic Y220C mutant. Chem. Biol. 17, 46–56 (2010).
Bykov, V. J. et al. Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nature Med. 8, 282–288 (2002).
Zache, N., Lambert, J. M., Wiman, K. G. & Bykov, V. J. PRIMA-1MET inhibits growth of mouse tumors carrying mutant p53. Cell Oncol. 30, 411–418 (2008).
Zandi, R. et al. PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53. Clin. Cancer Res. 17, 2830–2841 (2011).
Lehmann, S. et al. Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J. Clin. Oncol. 30, 3633–3639 (2012).
Lambert, J. M. et al. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell 15, 376–388 (2009).
Kaar, J. L. et al. Stabilization of mutant p53 via alkylation of cysteines and effects on DNA binding. Protein Sci. 19, 2267–2278 (2010).
Wassman, C. D. et al. Computational identification of a transiently open L1/S3 pocket for reactivation of mutant p53. Nature Commun. 4, 1407 (2013).
Scotcher, J. et al. Identification of two reactive cysteine residues in the tumor suppressor protein p53 using top-down FTICR mass spectrometry. J. Am. Soc. Mass Spectrom. 22, 888–897 (2011).
Held, J. M. et al. Targeted quantitation of site-specific cysteine oxidation in endogenous proteins using a differential alkylation and multiple reaction monitoring mass spectrometry approach. Mol. Cell Proteom. 9, 1400–1410 (2010).
Shalom-Feuerstein, R. et al. Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1MET. Proc. Natl Acad. Sci. USA 110, 2152–2156 (2013).
Shen, J. et al. APR-246/PRIMA-1(MET) rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations. Proc. Natl Acad. Sci. USA 110, 2157–2162 (2013).
Rokaeus, N. et al. PRIMA-1(MET)/APR-246 targets mutant forms of p53 family members p63 and p73. Oncogene 29, 6442–6451 (2010).
Stegh, A. H. Targeting the p53 signaling pathway in cancer therapy — the promises, challenges and perils. Expert Opin. Ther. Targets 16, 67–83 (2012).
Cho, Y., Gorina, S., Jeffrey, P. D. & Pavletich, N. P. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 265, 346–355 (1994).
Loh, S. N. The missing zinc: p53 misfolding and cancer. Metallomics 2, 442–449 (2010).
Joerger, A. C. & Fersht, A. R. Structure-function-rescue: the diverse nature of common p53 cancer mutants. Oncogene 26, 2226–2242 (2007).
Puca, R., Nardinocchi, L., Givol, D. & D'Orazi, G. Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells. Oncogene 29, 4378–4387 (2010).
Puca, R. et al. Restoring p53 active conformation by zinc increases the response of mutant p53 tumor cells to anticancer drugs. Cell Cycle 10, 1679–1689 (2011).
Issaeva, N. et al. Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nature Med. 10, 1321–1328 (2004).
Azmi, A. S. et al. MI-219-zinc combination: a new paradigm in MDM2 inhibitor-based therapy. Oncogene 30, 117–126 (2011).
Yu, X., Vazquez, A., Levine, A. J. & Carpizo, D. R. Allele-specific p53 mutant reactivation. Cancer Cell 21, 614–625 (2012).
Linde, L. & Kerem, B. Introducing sense into nonsense in treatments of human genetic diseases. Trends Genet. 24, 552–563 (2008).
Rowe, S. M. & Clancy, J. P. Pharmaceuticals targeting nonsense mutations in genetic diseases: progress in development. BioDrugs 23, 165–174 (2009).
Floquet, C., Deforges, J., Rousset, J. P. & Bidou, L. Rescue of non-sense mutated p53 tumor suppressor gene by aminoglycosides. Nucleic Acids Res. 39, 3350–3362 (2011).
Sermet-Gaudelus, I. et al. Ataluren (PTC124) induces cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis. Am. J. Respir. Crit. Care Med. 182, 1262–1272 (2010).
Kerem, E. et al. Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet 372, 719–727 (2008).
Auld, D. S. et al. Molecular basis for the high-affinity binding and stabilization of firefly luciferase by PTC124. Proc. Natl Acad. Sci. USA 107, 4878–4883 (2010).
Auld, D. S., Thorne, N., Maguire, W. F. & Inglese, J. Mechanism of PTC124 activity in cell-based luciferase assays of nonsense codon suppression. Proc. Natl Acad. Sci. USA 106, 3585–3590 (2009).
Kayali, R. et al. Read-through compound 13 restores dystrophin expression and improves muscle function in the mdx mouse model for Duchenne muscular dystrophy. Hum. Mol. Genet. 21, 4007–4020 (2012).
Choong, M. L., Yang, H., Lee, M. A. & Lane, D. P. Specific activation of the p53 pathway by low dose actinomycin D: a new route to p53 based cyclotherapy. Cell Cycle 8, 2810–2818 (2009).
MacCallum, D. E. et al. Seliciclib (CYC202, R-roscovitine) induces cell death in multiple myeloma cells by inhibition of RNA polymerase II-dependent transcription and down-regulation of Mcl-1. Cancer Res. 65, 5399–5407 (2005).
Smart, P. et al. Effects on normal fibroblasts and neuroblastoma cells of the activation of the p53 response by the nuclear export inhibitor leptomycin B. Oncogene 18, 7378–7386 (1999).
Blank, J. L. et al. Novel DNA damage checkpoints mediating cell death induced by the NEDD8-activating enzyme inhibitor MLN4924. Cancer Res. 73, 225–234 (2013).
Li, L. et al. Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell 21, 266–281 (2012).
Rigatti, M. J., Verma, R., Belinsky, G. S., Rosenberg, D. W. & Giardina, C. Pharmacological inhibition of Mdm2 triggers growth arrest and promotes DNA breakage in mouse colon tumors and human colon cancer cells. Mol. Carcinog. 51, 363–378 (2012).
Verma, R., Rigatti, M. J., Belinsky, G. S., Godman, C. A. & Giardina, C. DNA damage response to the Mdm2 inhibitor nutlin-3. Biochem. Pharmacol. 79, 565–574 (2010).
Secchiero, P. et al. The MDM-2 antagonist nutlin-3 promotes the maturation of acute myeloid leukemic blasts. Neoplasia 9, 853–861 (2007).
Shin, J. S. et al. Structural insights into the dual-targeting mechanism of Nutlin-3. Biochem. Biophys. Res. Commun. 420, 48–53 (2012).
Long, J. et al. Multiple distinct molecular mechanisms influence sensitivity and resistance to MDM2 inhibitors in adult acute myelogenous leukemia. Blood 116, 71–80 (2010).
Secchiero, P. et al. Functional integrity of the p53-mediated apoptotic pathway induced by the nongenotoxic agent nutlin-3 in B-cell chronic lymphocytic leukemia (B-CLL). Blood 107, 4122–4129 (2006).
Saha, M. N., Jiang, H. & Chang, H. Molecular mechanisms of nutlin-induced apoptosis in multiple myeloma: evidence for p53-transcription-dependent and -independent pathways. Cancer Biol. Ther. 10, 567–578 (2010).
Van Maerken, T. et al. Antitumor activity of the selective MDM2 antagonist nutlin-3 against chemoresistant neuroblastoma with wild-type p53. J. Natl Cancer Inst. 101, 1562–1574 (2009).
Tabe, Y. et al. MDM2 antagonist nutlin-3 displays antiproliferative and proapoptotic activity in mantle cell lymphoma. Clin. Cancer Res. 15, 933–942 (2009).
Momand, J., Jung, D., Wilczynski, S. & Niland, J. The MDM2 gene amplification database. Nucleic Acids Res. 26, 3453–3459 (1998).
Ohnstad, H. O. et al. Correlation of TP53 and MDM2 genotypes with response to therapy in sarcoma. Cancer 119, 1013–1022 (2013).
Tovar, C. et al. Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy. Proc. Natl Acad. Sci. USA 103, 1888–1893 (2006).
Paris, R., Henry, R. E., Stephens, S. J., McBryde, M. & Espinosa, J. M. Multiple p53-independent gene silencing mechanisms define the cellular response to p53 activation. Cell Cycle 7, 2427–2433 (2008).
Gutekunst, M. et al. p53 hypersensitivity is the predominant mechanism of the unique responsiveness of testicular germ cell tumor (TGCT) cells to cisplatin. PLoS ONE 6, e19198 (2011).
Gutekunst, M. et al. Cisplatin hypersensitivity of testicular germ cell tumors is determined by high constitutive Noxa levels mediated by Oct-4. Cancer Res. 73, 1460–1469 (2013).
Ross, C. J. et al. Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy. Nature Genet. 41, 1345–1349 (2009).
Kracikova, M., Akiri, G., George, A., Sachidanandam, R. & Aaronson, S. A. A threshold mechanism mediates p53 cell fate decision between growth arrest and apoptosis. Cell Death Differ. 20, 576–588 (2013). This is a careful, quantitative analysis of p53 signal intensity and the duration needed to cross the apoptotic threshold.
Tovar, C. et al. MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models. Cancer Res. 73, 2587–2597 (2013).
Ray-Coquard, I. et al. Effect of the MDM2 antagonist RG7112 on the p53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol. 13, 1133–1140 (2012). This is the first description of the clinical trial of MDM2 inhibitors in the treatment of sarcoma.
Soucek, L. et al. Modelling Myc inhibition as a cancer therapy. Nature 455, 679–683 (2008).
Carter, B. Z. et al. Simultaneous activation of p53 and inhibition of XIAP enhance the activation of apoptosis signaling pathways in AML. Blood 115, 306–314 (2010).
Valentine, J. M., Kumar, S. & Moumen, A. A p53-independent role for the MDM2 antagonist Nutlin-3 in DNA damage response initiation. BMC Cancer 11, 79 (2011).
Iancu-Rubin, C. et al. Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis. Exp. Hematol. http://dx.doi.org/10.1016/j.exphem.2013.11.012 (2013).
Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).
Michaelis, M. et al. Adaptation of cancer cells from different entities to the MDM2 inhibitor nutlin-3 results in the emergence of p53-mutated multi-drug-resistant cancer cells. Cell Death Dis. 2, e243 (2011).
Aziz, M. H., Shen, H. & Maki, C. G. Acquisition of p53 mutations in response to the non-genotoxic p53 activator Nutlin-3. Oncogene 30, 4678–4686 (2011).
Jones, R. J., Bjorklund, C. C., Baladandayuthapani, V., Kuhn, D. J. & Orlowski, R. Z. Drug resistance to inhibitors of the human double minute-2 E3 ligase is mediated by point mutations of p53, but can be overcome with the p53 targeting agent RITA. Mol. Cancer Ther. 11, 2243–2253 (2012).
Brummelkamp, T. R. et al. An shRNA barcode screen provides insight into cancer cell vulnerability to MDM2 inhibitors. Nature Chem. Biol. 2, 202–206 (2006).
Shchors, K. et al. Using a preclinical mouse model of high-grade astrocytoma to optimize p53 restoration therapy. Proc. Natl Acad. Sci. USA 110, E1480–E1489 (2013).
Rudin, C. M. et al. Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin. Cancer Res. 18, 3163–3169 (2012).
Roberts, A. W. et al. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J. Clin. Oncol. 30, 488–496 (2012).
van Delft, M. F. et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 10, 389–399 (2006).
Konopleva, M. et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 10, 375–388 (2006).
Yecies, D., Carlson, N. E., Deng, J. & Letai, A. Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1. Blood 115, 3304–3313 (2010).
Rooswinkel, R. W., van de Kooij, B., Verheij, M. & Borst, J. Bcl-2 is a better ABT-737 target than Bcl-xL or Bcl-w and only Noxa overcomes resistance mediated by Mcl-1, Bfl-1, or Bcl-B. Cell Death Dis. 3, e366 (2012).
Lew, Q. J. et al. NPMc+ AML cell line shows differential protein expression and lower sensitivity to DNA-damaging and p53-inducing anticancer compounds. Cell Cycle 10, 1978–1987 (2011).
Kojima, K., Konopleva, M., Samudio, I. J., Ruvolo, V. & Andreeff, M. Mitogen-activated protein kinase kinase inhibition enhances nuclear proapoptotic function of p53 in acute myelogenous leukemia cells. Cancer Res. 67, 3210–3219 (2007).
Konopleva, M. et al. MEK inhibition enhances ABT-737-induced leukemia cell apoptosis via prevention of ERK-activated MCL-1 induction and modulation of MCL-1/BIM complex. Leukemia 26, 778–787 (2012).
Glaser, S. P. et al. Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia. Genes Dev. 26, 120–125 (2012).
Vo, T. T. et al. Relative mitochondrial priming of myeloblasts and normal HSCs determines chemotherapeutic success in AML. Cell 151, 344–355 (2012).
Ni Chonghaile, T. et al. Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science 334, 1129–1133 (2011).
Patton, J. T. et al. Levels of HdmX expression dictate the sensitivity of normal and transformed cells to Nutlin-3. Cancer Res. 66, 3169–3176 (2006).
Wade, M., Wong, E. T., Tang, M., Stommel, J. M. & Wahl, G. M. Hdmx modulates the outcome of p53 activation in human tumor cells. J. Biol. Chem. 281, 33036–33044 (2006).
Garcia, D. et al. Validation of MdmX as a therapeutic target for reactivating p53 in tumors. Genes Dev. 25, 1746–1757 (2011).
Wei, S. J. Inhibition of Nutlin-resistant HDM2 mutants by stapled peptides. PLoS ONE 8, e81068 (2013).
Michaelis, M. et al. Reversal of P-glycoprotein-mediated multidrug resistance by the murine double minute 2 antagonist nutlin-3. Cancer Res. 69, 416–421 (2009).
Ribas, J., Boix, J. & Meijer, L. (R)-roscovitine (CYC202, seliciclib) sensitizes SH-SY5Y neuroblastoma cells to nutlin-3-induced apoptosis. Exp. Cell Res. 312, 2394–2400 (2006).
Cheok, C. F., Dey, A. & Lane, D. P. Cyclin-dependent kinase inhibitors sensitize tumor cells to nutlin-induced apoptosis: a potent drug combination. Mol. Cancer Res. 5, 1133–1145 (2007).
Kojima, K., Konopleva, M., Tsao, T., Nakakuma, H. & Andreeff, M. Concomitant inhibition of Mdm2-p53 interaction and Aurora kinases activates the p53-dependent postmitotic checkpoints and synergistically induces p53-mediated mitochondrial apoptosis along with reduced endoreduplication in acute myelogenous leukemia. Blood 112, 2886–2895 (2008).
Cheok, C. F., Kua, N., Kaldis, P. & Lane, D. P. Combination of nutlin-3 and VX-680 selectively targets p53 mutant cells with reversible effects on cells expressing wild-type p53. Cell Death Differ. 17, 1486–1500 (2010).
Coll-Mulet, L. et al. MDM2 antagonists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells. Blood 107, 4109–4114 (2006).
Cao, C. et al. Radiosensitization of lung cancer by nutlin, an inhibitor of murine double minute 2. Mol. Cancer Ther. 5, 411–417 (2006).
Supiot, S., Hill, R. P. & Bristow, R. G. Nutlin-3 radiosensitizes hypoxic prostate cancer cells independent of p53. Mol. Cancer Ther. 7, 993–999 (2008).
Zhang, W. et al. Blockade of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase and murine double minute synergistically induces apoptosis in acute myeloid leukemia via BH3-only proteins Puma and Bim. Cancer Res. 70, 2424–2434 (2010).
Thompson, T., Andreeff, M., Studzinski, G. P. & Vassilev, L. T. 1,25-dihydroxyvitamin D3 enhances the apoptotic activity of MDM2 antagonist nutlin-3a in acute myeloid leukemia cells expressing wild-type p53. Mol. Cancer Ther. 9, 1158–1168 (2010).
McCormack, E. et al. Synergistic induction of p53 mediated apoptosis by valproic acid and nutlin-3 in acute myeloid leukemia. Leukemia 26, 910–917 (2012).
Li, M., Luo, J., Brooks, C. L. & Gu, W. Acetylation of p53 inhibits its ubiquitination by Mdm2. J. Biol. Chem. 277, 50607–50611 (2002).
Wade, M., Rodewald, L. W., Espinosa, J. M. & Wahl, G. M. BH3 activation blocks Hdmx suppression of apoptosis and cooperates with Nutlin to induce cell death. Cell Cycle 7, 1973–1982 (2008).
Kojima, K. et al. Concomitant inhibition of MDM2 and Bcl-2 protein function synergistically induce mitochondrial apoptosis in AML. Cell Cycle 5, 2778–2786 (2006).
Mir, R. et al. Mdm2 antagonists induce apoptosis and synergize with cisplatin overcoming chemoresistance in TP53 wild-type ovarian cancer cells. Int. J. Cancer 132, 1525–1536 (2013).
Tovar, C. et al. MDM2 antagonists boost antitumor effect of androgen withdrawal: implications for therapy of prostate cancer. Mol. Cancer 10, 49 (2011).
Konopleva, M. et al. Stromal cells prevent apoptosis of AML cells by up-regulation of anti-apoptotic proteins. Leukemia 16, 1713–1724 (2002).
Davids, M. S. et al. Decreased mitochondrial apoptotic priming underlies stroma-mediated treatment resistance in chronic lymphocytic leukemia. Blood 120, 3501–3509 (2012).
Sullivan, K. D. et al. ATM and MET kinases are synthetic lethal with nongenotoxic activation of p53. Nature Chem. Biol. 8, 646–654 (2012).
Zauli, G. et al. Dasatinib plus Nutlin-3 shows synergistic antileukemic activity in both p53 wild-type and p53 mutated B chronic lymphocytic leukemias by inhibiting the Akt pathway. Clin. Cancer Res. 17, 762–770 (2011).
Zauli, G. et al. The sorafenib plus nutlin-3 combination promotes synergistic cytotoxicity in acute myeloid leukemic cells irrespectively of FLT3 and p53 status. Haematologica 97, 1722–1730 (2012).
Lehmann, B. D. et al. A dominant role for p53-dependent cellular senescence in radiosensitization of human prostate cancer cells. Cell Cycle 6, 595–605 (2007).
Blagosklonny, M. V. & Pardee, A. B. Exploiting cancer cell cycling for selective protection of normal cells. Cancer Res. 61, 4301–4305 (2001).
Blagosklonny, M. V. & Pardee, A. B. The restriction point of the cell cycle. Cell Cycle 1, 103–110 (2002).
Carvajal, D. et al. Activation of p53 by MDM2 antagonists can protect proliferating cells from mitotic inhibitors. Cancer Res. 65, 1918–1924 (2005).
Kranz, D. & Dobbelstein, M. Nongenotoxic p53 activation protects cells against S-phase-specific chemotherapy. Cancer Res. 66, 10274–10280 (2006).
Lane, D. P. Cancer. p53, guardian of the genome. Nature 358, 15–16 (1992).
van Leeuwen, I. M., Rao, B., Sachweh, M. C. & Lain, S. An evaluation of small-molecule p53 activators as chemoprotectants ameliorating adverse effects of anticancer drugs in normal cells. Cell Cycle 11, 1851–1861 (2012).
van Leeuwen, I. M. Cyclotherapy: opening a therapeutic window in cancer treatment. Oncotarget 3, 596–600 (2012).
Sur, S. et al. A panel of isogenic human cancer cells suggests a therapeutic approach for cancers with inactivated p53. Proc. Natl Acad. Sci. USA 106, 3964–3969 (2009).
Oda, K. et al. p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53. Cell 102, 849–862 (2000).
Chen, X. & Ko, L. J., Jayaraman, L. & Prives, C. p53 levels, functional domains, and DNA damage determine the extent of the apoptotic response of tumor cells. Genes Dev. 10, 2438–2451 (1996).
Veprintsev, D. B. & Fersht, A. R. Algorithm for prediction of tumour suppressor p53 affinity for binding sites in DNA. Nucleic Acids Res. 36, 1589–1598 (2008).
Schlereth, K. et al. DNA binding cooperativity of p53 modulates the decision between cell-cycle arrest and apoptosis. Mol. Cell 38, 356–368 (2010).
Schlereth, K., Charles, J. P., Bretz, A. C. & Stiewe, T. Life or death: 53-induced apoptosis requires DNA binding cooperativity. Cell Cycle 9, 4068–4076 (2010).
Timofeev, O. et al. p53 DNA binding cooperativity is essential for apoptosis and tumor suppression in vivo. Cell Rep. 3, 1512–1525 (2013).
Samuels-Lev, Y. et al. ASPP proteins specifically stimulate the apoptotic function of p53. Mol. Cell 8, 781–794 (2001).
Bergamaschi, D. et al. iASPP preferentially binds p53 proline-rich region and modulates apoptotic function of codon 72-polymorphic p53. Nature Genet. 38, 1133–1141 (2006).
Zhang, X., Wang, M., Zhou, C., Chen, S. & Wang, J. The expression of iASPP in acute leukemias. Leuk. Res. 29, 179–183 (2005).
Jiang, L. et al. iASPP and chemoresistance in ovarian cancers: effects on paclitaxel-mediated mitotic catastrophe. Clin. Cancer Res. 17, 6924–6933 (2011).
Kruse, J. P. & Gu, W. Modes of p53 regulation. Cell 137, 609–622 (2009).
Lane, D. P., Brown, C. J., Verma, C. & Cheok, C. F. New insights into p53 based therapy. Discov. Med. 12, 107–117 (2011).
Gannon, H. S., Woda, B. A. & Jones, S. N. ATM phosphorylation of Mdm2 Ser394 regulates the amplitude and duration of the DNA damage response in mice. Cancer Cell 21, 668–679 (2012).
Sakaguchi, K. et al. Damage-mediated phosphorylation of human p53 threonine 18 through a cascade mediated by a casein 1-like kinase. Effect on Mdm2 binding. J. Biol. Chem. 275, 9278–9283 (2000).
D'Orazi, G. et al. Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis. Nature Cell Biol. 4, 11–19 (2002).
Hofmann, T. G. et al. Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2. Nature Cell Biol. 4, 1–10 (2002).
Ma, T. et al. Inability of p53-reactivating compounds Nutlin-3 and RITA to overcome p53 resistance in tumor cells deficient in p53Ser46 phosphorylation. Biochem. Biophys. Res. Commun. 417, 931–937 (2012).
Henry, R. E., Andrysik, Z., Paris, R., Galbraith, M. D. & Espinosa, J. M. A. DR4:tBID axis drives the p53 apoptotic response by promoting oligomerization of poised BAX. EMBO J. 31, 1266–1278 (2012).
Michalak, E. M., Villunger, A., Adams, J. M. & Strasser, A. In several cell types tumour suppressor p53 induces apoptosis largely via Puma but Noxa can contribute. Cell Death Differ. 15, 1019–1029 (2008).
Happo, L. et al. Maximal killing of lymphoma cells by DNA damage-inducing therapy requires not only the p53 targets Puma and Noxa, but also Bim. Blood 116, 5256–5267 (2010).
Chen, L. et al. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol. Cell 17, 393–403 (2005).
Mihara, M. et al. p53 has a direct apoptogenic role at the mitochondria. Mol. Cell 11, 577–590 (2003).
Chipuk, J. E. et al. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303, 1010–1014 (2004).
Lujambio, A. et al. Non-cell-autonomous tumor suppression by p53. Cell 153, 449–460 (2013).
Jackson, J. G. et al. p53-mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer. Cancer Cell 21, 793–806 (2012).
Vassilev, L. T. Small-molecule antagonists of p53-MDM2 binding: research tools and potential therapeutics. Cell Cycle 3, 419–421 (2004).
Uoto, K. et al. Imidazothiazole derivative having 4,7-diazaspiro [2.5] octane ring structure. WO Patent 2009151069A1 (2009).
Koblish, H. K. et al. Benzodiazepinedione inhibitors of the Hdm2:p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo. Mol. Cancer Ther. 5, 160–169 (2006).
Secchiero, P., Vaccarezza, M., Gonelli, A. & Zauli, G. TNF-related apoptosis-inducing ligand (TRAIL): a potential candidate for combined treatment of hematological malignancies. Curr. Pharm. Des. 10, 3673–3681 (2004).
Vatsyayan, R., Singhal, J., Nagaprashantha, L. D., Awasthi, S. & Singhal, S. S. Nutlin-3 enhances sorafenib efficacy in renal cell carcinoma. Mol. Carcinog. 52, 39–48 (2013).
Kojima, K. et al. Prognostic impact and targeting of CRM1 in acute myeloid leukemia. Blood 121, 4166–4174 (2013).
The authors declare no competing financial interests.
About this article
Cite this article
Khoo, K., Verma, C. & Lane, D. Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Discov 13, 217–236 (2014). https://doi.org/10.1038/nrd4236
Signal Transduction and Targeted Therapy (2020)
ACS Chemical Biology (2020)
Cell Reports (2020)
Acta Pharmaceutica Sinica B (2020)