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Small-molecule activation of the TRAIL receptor DR5 in human cancer cells


Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) activates apoptosis through the death receptors DR4 and DR5. Because of its superior safety profile and high tumor specificity compared to other TNF family members, recombinant soluble TRAIL and agonistic antibodies against its receptors are actively being developed for clinical cancer therapy. Here, we describe the identification and characterization of the small molecules that directly target DR5 to initiate apoptosis in human cancer cells. The activity was initially discovered through a high-throughput chemical screen for compounds that promote cell death in synergy with a small-molecule mimetic of Smac, the antagonist for inhibitor of apoptosis protein. Structure-activity relationship studies yielded a more potent analog called bioymifi, which can act as a single agent to induce DR5 clustering and aggregation, leading to apoptosis. Thus, this study identified potential lead compounds for the development of small-molecule TRAIL mimics targeting DR5 for cancer therapy.

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Figure 1: Identification and chemical elucidation of the Smac synergists from the chemical library screen.
Figure 2: A functional analog of A2C2, bioymifi induces apoptosis.
Figure 3: Bioymifi-induced apoptosis occurs through a DR5-dependent extrinsic pathway.
Figure 4: Bioymifi promotes cell death independent of TRAIL.
Figure 5: Bioymifi selectively binds the ECD of DR5.
Figure 6: Bioymifi and A2C2 promote DR5 aggregation and activation.


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We thank M. Zhao for NMR and HPLC/MS analysis; S.L. Petersen for reagents and discussions; L. Zhao for the toxicological experiments; S.L. McKnight for helpful suggestions; M. Roth for proposing the chemical library screen; D. Frantz, J. Ready and A. Wang for synthesis of initial hits; Y. Liu, Z. Zhang, Q. Liu and L. Shang for comments of the manuscript; S.-C. Tso and T. Scheuermann for detecting the interaction between DR5 and bioymifi; and K. Phelps and A. Budge for the cell imaging. This work is supported by a program project grant from the US National Cancer Institute (2P01 CA095471-06 to Xiaodong Wang and G.W.) and the National Natural Science Foundation of China (21072150 and 21222209 to X.L.).

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Authors and Affiliations



Xiaodong Wang, X.L. and G.W. designed the study; G.W., H.Y., N.W., D.L.H., R.H., L.L. and L.W. performed and analyzed the biological experiments; Xiaoming Wang, J.N., P.H. and X.L. performed all of the chemical syntheses; S.C. performed the MS analysis; S.W. implemented the chemical library screen; and Xiaodong Wang, X.L. and G.W. wrote the manuscript.

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Correspondence to Gelin Wang, Xiaoguang Lei or Xiaodong Wang.

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The authors declare no competing financial interests.

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Wang, G., Wang, X., Yu, H. et al. Small-molecule activation of the TRAIL receptor DR5 in human cancer cells. Nat Chem Biol 9, 84–89 (2013).

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