5TBM

Crystal structure of PT2385 bound to HIF2a-B*:ARNT-B* complex

Summary for 5TBM

• Entry DOI: 10.2210/pdb5tbm/pdb
• Descriptor: Endothelial PAS domain-containing protein 1, Aryl hydrocarbon receptor nuclear translocator, 3-{[(1S)-2,2-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl]oxy}-5-fluorobenzonitrile, ... (4 entities in total)
• Functional Keywords: hif2 inhibitor hif2 ligand pas-b hypoxia inducible factor 2 epas1, transcription
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : Q99814 P27540
• Total number of polymer chains: 2
• Total formula weight: 27431.94

Authors

Du, X. (deposition date: 2016-09-12, release date: 2016-09-21, Last modification date: 2023-10-04)

Primary citation

Wallace, E.M.,Rizzi, J.P.,Han, G.,Wehn, P.M.,Cao, Z.,Du, X.,Cheng, T.,Czerwinski, R.M.,Dixon, D.D.,Goggin, B.S.,Grina, J.A.,Halfmann, M.M.,Maddie, M.A.,Olive, S.R.,Schlachter, S.T.,Tan, H.,Wang, B.,Wang, K.,Xie, S.,Xu, R.,Yang, H.,Josey, J.A.
A Small-Molecule Antagonist of HIF2 alpha Is Efficacious in Preclinical Models of Renal Cell Carcinoma.
Cancer Res., 76:5491-5500, 2016

PubMed Abstract: More than 90% of clear cell renal cell carcinomas (ccRCC) exhibit inactivation of the von Hippel-Lindau (pVHL) tumor suppressor, establishing it as the major underlying cause of this malignancy. pVHL inactivation results in stabilization of the hypoxia-inducible transcription factors, HIF1α and HIF2α, leading to expression of a genetic program essential for the initiation and progression of ccRCC. Herein, we describe the potent, selective, and orally active small-molecule inhibitor PT2385 as a specific antagonist of HIF2α that allosterically blocks its dimerization with the HIF1α/2α transcriptional dimerization partner ARNT/HIF1β. PT2385 inhibited the expression of HIF2α-dependent genes, including VEGF-A, PAI-1, and cyclin D1 in ccRCC cell lines and tumor xenografts. Treatment of tumor-bearing mice with PT2385 caused dramatic tumor regressions, validating HIF2α as a pivotal oncogenic driver in ccRCC. Notably, unlike other anticancer agents that inhibit VEGF receptor signaling, PT2385 exhibited no adverse effect on cardiovascular performance. Thus, PT2385 represents a novel class of therapeutics for the treatment of RCC with potent preclincal efficacy as well as improved tolerability relative to current agents that target the VEGF pathway. Cancer Res; 76(18); 5491-500. ©2016 AACR.

PubMed: 27635045
DOI: 10.1158/0008-5472.CAN-16-0473

Experimental method

X-RAY DIFFRACTION (1.85 Å)