Targeting BCR/ABL with tyrosine kinase inhibitors (TKIs) is a proven concept for the treatment of Philadelphia chromosome-positive (Ph+) leukemias. Resistance attributable to either kinase mutations in BCR/ABL or nonmutational mechanisms remains the major clinical challenge. With the exception of ponatinib, all approved TKIs are unable to inhibit the ‘gatekeeper’ mutation T315I. However, a broad spectrum of kinase inhibition increases the off-target effects of TKIs and may be responsible for cardiovascular issues of ponatinib. Thus, there is a need for more selective options for the treatment of resistant Ph+ leukemias. PF-114 is a novel TKI developed with the specifications of (i) targeting T315I and other resistance mutations in BCR/ABL; (ii) achieving a high selectivity to improve safety; and (iii) overcoming nonmutational resistance in Ph+ leukemias. PF-114 inhibited BCR/ABL and clinically important mutants including T315I at nanomolar concentrations. It suppressed primary Ph+ acute lymphatic leukemia-derived long-term cultures that either displayed nonmutational resistance or harbor the T315I. In BCR/ABL- or BCR/ABL–T315I-driven murine leukemia as well as in xenograft models of primary Ph+ leukemia harboring the T315I, PF-114 significantly prolonged survival to a similar extent as ponatinib. Our work supports clinical evaluation of PF-114 for the treatment of resistant Ph+ leukemia.
Subscribe to Journal
Get full journal access for 1 year
only $102.00 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.
Hughes TP, Hochhaus A, Branford S, Muller MC, Kaeda JS, Foroni L et al. Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood 2010; 116: 3758–3765.
Hoglund M, Sandin F, Hellstrom K, Bjoreman M, Bjorkholm M, Brune M et al. Tyrosine kinase inhibitor usage, treatment outcome, and prognostic scores in CML: report from the population-based Swedish CML registry. Blood 2013; 122: 1284–1292.
Talpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini C, Guilhot F et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 2002; 99: 1928–1937.
Giles FJ, Kantarjian HM, le Coutre PD, Baccarani M, Mahon FX, Blakesley RE et al. Nilotinib is effective in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blastic phase. Leukemia 2012; 26: 959–962.
Ottmann OG, Larson RA, Kantarjian HM, le Coutre PD, Baccarani M, Hochhaus A et al. Phase II study of nilotinib in patients with relapsed or refractory Philadelphia chromosome—positive acute lymphoblastic leukemia. Leukemia 2013; 27: 1411–1413.
Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006; 355: 2408–2417.
O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348: 994–1004.
Soverini S, Iacobucci I, Baccarani M, Martinelli G . Targeted therapy and the T315I mutation in Philadelphia-positive leukemias. Haematologica 2007; 92: 437–439.
Branford S, Hughes TP . Mutational analysis in chronic myeloid leukemia: when and what to do? Curr Opin Hematol 2011; 18: 111–116.
Pfeifer H, Wassmann B, Pavlova A, Wunderle L, Oldenburg J, Binckebanck A et al. Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood 2007; 110: 727–734.
Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2002; 2: 117–125.
Soverini S, Colarossi S, Gnani A, Rosti G, Castagnetti F, Poerio A et al. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin Cancer Res 2006; 12: 7374–7379.
Hughes T, Saglio G, Branford S, Soverini S, Kim DW, Muller MC et al. Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol 2009; 27: 4204–4210.
Muller MC, Cortes JE, Kim DW, Druker BJ, Erben P, Pasquini R et al. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood 2009; 114: 4944–4953.
Cortes JE, Jones D, O'Brien S, Jabbour E, Konopleva M, Ferrajoli A et al. Nilotinib as front-line treatment for patients with chronic myeloid leukemia in early chronic phase. J Clin Oncol 2010; 28: 392–397.
Cortes JE, Jones D, O'Brien S, Jabbour E, Ravandi F, Koller C et al. Results of dasatinib therapy in patients with early chronic-phase chronic myeloid leukemia. J Clin Oncol 2010; 28: 398–404.
Cortes JE, Kim DW, Kantarjian HM, Brummendorf TH, Dyagil I, Griskevicius L et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol 2012; 30: 3486–3492.
Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2010; 362: 2260–2270.
Rosti G, Palandri F, Castagnetti F, Breccia M, Levato L, Gugliotta G et al. Nilotinib for the frontline treatment of Ph(+) chronic myeloid leukemia. Blood 2009; 114: 4933–4938.
Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010; 362: 2251–2259.
Cortes J, Jabbour E, Kantarjian H, Yin CC, Shan J, O'Brien S et al. Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors. Blood 2007; 110: 4005–4011.
Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 2007; 110: 3540–3546.
Shah NP, Skaggs BJ, Branford S, Hughes TP, Nicoll JM, Paquette RL et al. Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency. J Clin Invest 2007; 117: 2562–2569.
Nicolini FE, Corm S, Le QH, Sorel N, Hayette S, Bories D et al. Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(phi)-LMC GROUP). Leukemia 2006; 20: 1061–1066.
Nicolini FE, Hayette S, Corm S, Bachy E, Bories D, Tulliez M et al. Clinical outcome of 27 imatinib mesylate-resistant chronic myelogenous leukemia patients harboring a T315I BCR-ABL mutation. Haematologica 2007; 92: 1238–1241.
O'Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 2009; 16: 401–412.
Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med 2012; 367: 2075–2088.
Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 2013; 369: 1783–1796.
Giles FJ, Cortes J, Jones D, Bergstrom D, Kantarjian H, Freedman SJ . MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation. Blood 2007; 109: 500–502.
Giles FJ, le Coutre PD, Pinilla-Ibarz J, Larson RA, Gattermann N, Ottmann OG et al. Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study. Leukemia 2013; 27: 107–112.
Tanaka R, Squires MS, Kimura S, Yokota A, Nagao R, Yamauchi T et al. Activity of the multitargeted kinase inhibitor, AT9283, in imatinib-resistant BCR-ABL-positive leukemic cells. Blood 2010; 116: 2089–2095.
Melo JV, Barnes DJ . Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nat Rev Cancer 2007; 7: 441–453.
Ottmann OG, Wassmann B . Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 2005, 118–122.
O'Hare T, Deininger MW, Eide CA, Clackson T, Druker BJ . Targeting the BCR-ABL signaling pathway in therapy-resistant Philadelphia chromosome-positive leukemia. Clin Cancer Res 2011; 17: 212–221.
Pfeifer H, Lange T, Wystub S, Wassmann B, Maier J, Binckebanck A et al. Prevalence and dynamics of bcr-abl kinase domain mutations during imatinib treatment differ in patients with newly diagnosed and recurrent bcr-abl positive acute lymphoblastic leukemia. Leukemia 2012; 26: 1475–1481.
Kimura S, Naito H, Segawa H, Kuroda J, Yuasa T, Sato K et al. NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia. Blood 2005; 106: 3948–3954.
von Bubnoff N, Barwisch S, Speicher MR, Peschel C, Duyster J . A cell-based screening strategy that predicts mutations in oncogenic tyrosine kinases: implications for clinical resistance in targeted cancer treatment. Cell Cycle 2005; 4: 400–406.
Zhou T, Commodore L, Huang WS, Wang Y, Thomas M, Keats J et al. Structural mechanism of the Pan-BCR-ABL inhibitor ponatinib (AP24534): lessons for overcoming kinase inhibitor resistance. Chem Biol Drug Des 2011; 77: 1–11.
Gould AE, Adams R, Adhikari S, Aertgeerts K, Afroze R, Blackburn C et al. Design and optimization of potent and orally bioavailable tetrahydronaphthalene Raf inhibitors. J Med Chem 2011; 54: 1836–1846.
Oguro Y, Miyamoto N, Okada K, Takagi T, Iwata H, Awazu Y et al. Design, synthesis, and evaluation of 5-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine derivatives: novel VEGFR2 kinase inhibitors binding to inactive kinase conformation. Bioorg Med Chem 2010; 18: 7260–7273.
Stroganov OV, Novikov FN, Zeifman AA, Stroylov VS, Chilov GG . TSAR, a new graph-theoretical approach to computational modeling of protein side-chain flexibility: modeling of ionization properties of proteins. Proteins 2011; 79: 2693–2710.
Stroganov OV, Novikov FN, Stroylov VS, Kulkov V, Chilov GG . Lead finder: an approach to improve accuracy of protein-ligand docking, binding energy estimation, and virtual screening. J Chem Inf Model 2008; 48: 2371–2385.
Pronk S, Pall S, Schulz R, Larsson P, Bjelkmar P, Apostolov R et al. GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics 2013; 29: 845–854.
Sousa da Silva AW, Vranken WF . ACPYPE - AnteChamber PYthon Parser interfacE. BMC Res Notes 2012; 5: 367.
Badura S, Tesanovic T, Pfeifer H, Wystub S, Nijmeijer BA, Liebermann M et al. Differential effects of selective inhibitors targeting the PI3K/AKT/mTOR pathway in acute lymphoblastic leukemia. PLoS One 2013; 8: e80070.
Mian AA, Oancea C, Zhao Z, Ottmann OG, Ruthardt M . Oligomerization inhibition, combined with allosteric inhibition, abrogates the transformation potential of T315I-positive BCR/ABL. Leukemia 2009; 23: 2242–2247.
Zheng X, Oancea C, Henschler R, Ruthardt M . Cooperation between constitutively activated c-Kit signaling and leukemogenic transcription factors in the determination of the leukemic phenotype in murine hematopoietic stem cells. Int J Oncol 2009; 34: 1521–1531.
Beissert T, Puccetti E, Bianchini A, Guller S, Boehrer S, Hoelzer D et al. Targeting of the N-terminal coiled coil oligomerization interface of BCR interferes with the transformation potential of BCR-ABL and increases sensitivity to STI571. Blood 2003; 102: 2985–2993.
Hochhaus A, Kreil S, Corbin AS, La Rosee P, Muller MC, Lahaye T et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 2002; 16: 2190–2196.
Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL . Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004; 305: 399–401.
Manley PW, Drueckes P, Fendrich G, Furet P, Liebetanz J, Martiny-Baron G et al. Extended kinase profile and properties of the protein kinase inhibitor nilotinib. Biochim Biophys Acta 2010; 1804: 445–453.
Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013; 122: 872–884.
Nijmeijer BA, Szuhai K, Goselink HM, van Schie ML, van der Burg M, de Jong D et al. Long-term culture of primary human lymphoblastic leukemia cells in the absence of serum or hematopoietic growth factors. Exp Hematol 2009; 37: 376–385.
Li S, Ilaria RL Jr., Million RP, Daley GQ, Van Etten RA . The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activity. J Exp Med 1999; 189: 1399–1412.
Mian AA, Metodieva A, Badura S, Khateb M, Ruimi N, Najajreh Y et al. Allosteric inhibition enhances the efficacy of ABL kinase inhibitors to target unmutated BCR-ABL and BCR-ABL-T315I. BMC Cancer 2012; 12: 411.
Bradeen HA, Eide CA, O'Hare T, Johnson KJ, Willis SG, Lee FY et al. Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)-based mutagenesis screen: high efficacy of drug combinations. Blood 2006; 108: 2332–2338.
Montani D, Bergot E, Gunther S, Savale L, Bergeron A, Bourdin A et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 2012; 125: 2128–2137.
Kantarjian H, le Coutre P, Cortes J, Pinilla-Ibarz J, Nagler A, Hochhaus A et al. Phase 1 study of INNO-406, a dual Abl/Lyn kinase inhibitor, in Philadelphia chromosome-positive leukemias after imatinib resistance or intolerance. Cancer 2010; 116: 2665–2672.
Le Coutre P, Rea D, Abruzzese E, Dombret H, Trawinska MM, Herndlhofer S et al. Severe peripheral arterial disease during nilotinib therapy. J Natl Cancer Inst 2011; 103: 1347–1348.
Burgess MR, Skaggs BJ, Shah NP, Lee FY, Sawyers CL . Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance. Proc Natl Acad Sci USA 2005; 102: 3395–3400.
The entire study was financed by Fusion Pharma LLC, Moscow, Russia. AZ, IT, VS, OS and GC are employees of Fusion Pharma. The remaining authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Leukemia website
About this article
Cite this article
Mian, A., Rafiei, A., Haberbosch, I. et al. PF-114, a potent and selective inhibitor of native and mutated BCR/ABL is active against Philadelphia chromosome-positive (Ph+) leukemias harboring the T315I mutation. Leukemia 29, 1104–1114 (2015) doi:10.1038/leu.2014.326
An Imatinib-non-responsive patient with an ABL Leu387Trp mutation achieves cytogenetic and molecular response under bosutinib: Case report and biological characterization
Clinical Case Reports (2019)
CDK4/CDK6 inhibition as a novel strategy to suppress the growth and survival of BCR-ABL1T315I+ clones in TKI-resistant CML
BCR-ABL1 tyrosine kinase inhibitor K0706 exhibits preclinical activity in Philadelphia chromosome-positive leukemia
Experimental Hematology (2019)
Current Opinion in Hematology (2019)
SLAS DISCOVERY: Advancing Life Sciences R&D (2019)