title: A Small-Molecule Antagonist of HIF2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma.
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.
authors.affiliation: Peloton Therapeutics, Inc., Dallas, Texas. eli.wallace@pelotontx.com.
authors.forename: Eli M
authors.initials: EM
authors.lastname: Wallace
authors.affiliation: Peloton Therapeutics, Inc., Dallas, Texas.
authors.forename: James P
authors.initials: JP
authors.lastname: Rizzi
authors.affiliation: Peloton Therapeutics, Inc., Dallas, Texas.
authors.forename: Guangzhou
authors.initials: G
authors.lastname: Han
authors.affiliation: Peloton Therapeutics, Inc., Dallas, Texas.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Wehn
authors.affiliation: Peloton Therapeutics, Inc., Dallas, Texas.
authors.forename: Zhaodan
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Peloton Therapeutics, Inc., Dallas, Texas.
authors.forename: Xinlin
authors.initials: X
authors.lastname: Du
authors.affiliation: Peloton Therapeutics, Inc., Dallas, Texas.
authors.forename: Tzuling
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Peloton Therapeutics, Inc., Dallas, Texas.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Czerwinski
authors.affiliation: Peloton Therapeutics, Inc., Dallas, Texas.
authors.forename: Darryl D
authors.initials: DD
authors.lastname: Dixon
authors.affiliation: Peloton Therapeutics, Inc., Dallas, Texas.
authors.forename: Barry S
authors.initials: BS
authors.lastname: Goggin
authors.affiliation: Peloton Therapeutics, Inc., Dallas, Texas.
authors.forename: Jonas A
authors.initials: JA
authors.lastname: Grina
authors.affiliation: Peloton Therapeutics, Inc., Dallas, Texas.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Halfmann
authors.affiliation: Peloton Therapeutics, Inc., Dallas, Texas.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Maddie
authors.affiliation: Peloton Therapeutics, Inc., Dallas, Texas.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Olive
authors.affiliation: Peloton Therapeutics, Inc., Dallas, Texas.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Schlachter
authors.affiliation: Peloton Therapeutics, Inc., Dallas, Texas.
authors.forename: Huiling
authors.initials: H
authors.lastname: Tan
authors.affiliation: Peloton Therapeutics, Inc., Dallas, Texas.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Peloton Therapeutics, Inc., Dallas, Texas.
authors.forename: Keshi
authors.initials: K
authors.lastname: Wang
authors.affiliation: Peloton Therapeutics, Inc., Dallas, Texas.
authors.forename: Shanhai
authors.initials: S
authors.lastname: Xie
authors.affiliation: Peloton Therapeutics, Inc., Dallas, Texas.
authors.forename: Rui
authors.initials: R
authors.lastname: Xu
authors.affiliation: Peloton Therapeutics, Inc., Dallas, Texas.
authors.forename: Hanbiao
authors.initials: H
authors.lastname: Yang
authors.affiliation: Peloton Therapeutics, Inc., Dallas, Texas.
authors.forename: John A
authors.initials: JA
authors.lastname: Josey
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors*; D002151:Calorimetry; D002292:Carcinoma, Renal Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007680:Kidney Neoplasms / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D016133:Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1