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A Small-Molecule Antagonist of Hif2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma

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A Small-Molecule Antagonist of Hif2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma Published OnlineFirst September 6, 2016; DOI: 10.1158/0008-5472.CAN-16-0473 Cancer Therapeutics, Targets, and Chemical Biology Research A Small-Molecule Antagonist of HIF2a Is Efficacious in Preclinical Models of Renal Cell Carcinoma Eli M. Wallace, James P. Rizzi, Guangzhou Han, Paul M. Wehn, Zhaodan Cao, Xinlin Du, Tzuling Cheng, Robert M. Czerwinski, Darryl D. Dixon, Barry S. Goggin, Jonas A. Grina, Megan M. Halfmann, Melissa A. Maddie, Sarah R. Olive, Stephen T. Schlachter, Huiling Tan, Bin Wang, Keshi Wang, Shanhai Xie, Rui Xu, Hanbiao Yang, and John A. Josey Abstract More than 90% of clear cell renal cell carcinomas (ccRCC) expression of HIF2a-dependent genes, including VEGF-A, exhibit inactivation of the von Hippel–Lindau (pVHL) tumor PAI-1, and cyclin D1 in ccRCC cell lines and tumor xenografts. suppressor, establishing it as the major underlying cause of this Treatment of tumor-bearing mice with PT2385 caused dramatic malignancy. pVHL inactivation results in stabilization of the tumor regressions, validating HIF2a as a pivotal oncogenic hypoxia-inducible transcription factors, HIF1a and HIF2a, driver in ccRCC. Notably, unlike other anticancer agents that leading to expression of a genetic program essential for the inhibit VEGF receptor signaling, PT2385 exhibited no adverse initiation and progression of ccRCC. Herein, we describe the effect on cardiovascular performance. Thus, PT2385 represents potent, selective, and orally active small-molecule inhibitor a novel class of therapeutics for the treatment of RCC with PT2385 as a specificantagonistofHIF2a that allosterically potent preclincal efficacy as well as improved tolerability rel- blocks its dimerization with the HIF1a/2a transcriptional ative to current agents that target the VEGF pathway. Cancer Res; dimerization partner ARNT/HIF1b. PT2385 inhibited the 76(18); 1–10. Ó2016 AACR. Introduction antagonists, inhibitors of mTOR, and immunomodulatory agents, such as inhibitors of PD-1. Few patients experience a Aberrant activation of transcription factors is frequently asso- complete response to these agents, and nearly all tumors progress ciated with pathophysiologic conditions, including cancer. Tran- during treatment (2). For patients with advanced or metastatic scription factors typically complex with other proteins and reg- ccRCC, the 5-year survival rate is only 8% (1). It is thus clear that ulate gene transcription by binding to specific DNA sequences. As better therapeutic options are needed. such, with the exception of nuclear hormone receptors, this class The HIFa family of transcription factors consists of HIF1a, of proteins has been perceived as intractable targets for pharma- HIF2a, and the less well characterized HIF3a (3–5). Under cologic intervention. HIF2a is one such protein that has been hypoxic conditions, HIFa proteins accumulate and translocate implicated in the initiation and progression of kidney cancer. to the nucleus, where they dimerize with ARNT. The HIFa–ARNT Nearly 64,000 new cases of kidney cancer were diagnosed in the heterodimers bind to the hypoxia-responsive elements (HRE) on United States in 2014, with approximately 70% being clear cell target genes whose products coordinately regulate anaerobic renal cell carcinoma (ccRCC; ref. 1). Patients with advanced metabolism, angiogenesis, cell proliferation and survival, extra- disease are currently treated with antiangiogenesis agents, such cellular matrix remodeling, pH homeostasis, amino acid and as multitargeted tyrosine kinase inhibitors and specific VEGF nucleotide metabolism, and genome stability (6–8). Under nor- moxic conditions, specific proline residues on the HIFa proteins are hydroxylated by the dioxygenase HIF-specific prolyl-hydro- Peloton Therapeutics, Inc., Dallas, Texas. xylases (9, 10). These posttranslational modifications serve as Note: Supplementary data for this article are available at Cancer Research recognition sites for the von Hippel–Lindau (pVHL) tumor sup- Online (http://cancerres.aacrjournals.org/). pressor protein, which binds to the hydroxylated proline residues Current address for D.D. Dixon: Bristol-Myers Squibb, New Brunswick, New as part of an E3 ubiquitin–ligase complex that then targets HIFa Jersey; current address for M.M. Halfmann: Stowers Institute for Medical proteins for proteasomal degradation. Research, Kansas City, Missouri; current address for M.A. Maddie: Renovo Neural, In more than 90% of ccRCC patients, pVHL is defective, caused Inc., Cleveland, Ohio; and current address for S.R. Olive: Progen Lab, Dallas, by gene deletion, mutation, epigenetic silencing, or posttransla- Texas. tional modifications (11), resulting in the stabilization of HIFa Corresponding Author: Eli M. Wallace, Peloton Therapeutics Inc., 2330 Inwood proteins. Over the last decade, accumulating data have suggested Road, Suite 226, Dallas, TX 75235. Phone: 972-629-4126; Fax: 972-629-4111; an oncogenic role for HIF2a in pVHL-defective ccRCC. In pVHL- E-mail: [email protected] defective ccRCC xenografts, knockdown of HIF2a expression doi: 10.1158/0008-5472.CAN-16-0473 inhibits tumor formation comparable with reintroduction of Ó2016 American Association for Cancer Research. functional VHL, and overexpression of a stabilized variant of www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst September 6, 2016; DOI: 10.1158/0008-5472.CAN-16-0473 Wallace et al. HIF2a alone is sufficient to overcome the tumor-suppressive 4-yl)oxy)-5-fluorobenzonitrile] (Fig. 1A), a HIF2a antagonist effect of pVHL (12–15). In contrast, HIF1a is often deleted or with potent antitumor activity. We also propose a mechanism mutated in ccRCC, and overexpression of HIF1a inhibited tumor by which this molecule inhibits HIF2a transcriptional activity. growth in pVHL-defective xenografts (12, 16, 17). These data suggest that HIF2a may be the tumorigenic driver in ccRCC and highlight the therapeutic potential of HIF2a antagonists for its Materials and Methods à à treatment. Crystallography of HIF2a-B :ARNT-B complex à à Biophysical studies have revealed a hydrophobic pocket in the The preparation of HIF2a-B :ARNT-B complex was described HIF2a PAS-B domain, leading to the discovery of a small mol- previously (20). The crystals of the heterodimer were produced by ecule that binds within the pocket and allosterically disrupts hanging drop vapor diffusion. The well solution contained 16% HIF2a dimerization to ARNT (18–19). Although this early work PEG 3350 and 50 mmol/L BisTris, pH 5.4, and the crystallization was seminal in identifying the possibility of antagonizing this drop was obtained by mixing 1 mL of well solution and 1 mLof transcription factor, the reported antagonists exhibit modest heterodimer at 12 mg/mL in 20 mmol/L Tris-HCl, pH 8.0, and 1 cellular potency and, most importantly, poor physical properties mmol/L DTT. Right after the mixing, crystal seeds from crushed that preclude their use in validating HIF2a as a target for treatment old crystals were transferred to the drop with a whisker. Diffrac- of ccRCC. Guided by iterative structure-based design utilizing the tion quality crystals typically grew after 2 or 3 days. For soaking, 5 heterodimer of PAS-B domains of HIF2a and ARNT, we have mL of the soaking solution, which consisted of 1 mmol/L PT2385, discovered potent HIF2a antagonists with excellent pharmaco- 20% PEG 3350, 5% DMSO, and 50 mmol/L Bis-Tris, pH 5.4, was logic properties, thereby enabling in vivo evaluation of this novel added to a crystal drop. Typically, soaking was carried out for 2 or anticancer mechanism. Here, we describe PT2385 [(S)-3-((2,2- 3 days before harvest. Freezing solution consisted of 1 mmol/L difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden- PT2385, 20% PEG 3350, 15% DMSO, and 50 mmol/L Bis-Tris, A F B F NC O OH O O S F PT2385 α C HIF2 HIF1α D PT2385 0.01 0.1 1 10 μmol/L DMSO ARNT HIF2α IP: HIF2α Kd = 0.049 μmol/L Figure 1. Binding of PT2385 to HIF2a PAS-B domain disrupts HIF2a/ARNT dimer formation. A, chemical structure of PT2385. Synthetic procedures, scheme, and characterization of PT2385 are available in Supplementary Methods. B, ribbon diagram of co-crystal structure of HIF2a PAS-Bà domain (green), ARNT PAS-Bà domain (blue), and PT2385 (magenta). C, binding affinity of PT2385 to PAS-B domains of human HIF2a and HIF1a using ITC. D, coimmunoprecipitation (IP) experiment in 786-O cells demonstrating PT2385 disrupts HIF2a and ARNT dimerization. OF2 Cancer Res; 76(18) September 15, 2016 Cancer Research Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst September 6, 2016; DOI: 10.1158/0008-5472.CAN-16-0473 PT2385: A Hypoxia-Inducible Factor-2a Antagonist pH 5.4. For harvest, crystals were briefly soaked in the freezing 20 mLof5 buffer (supplied with the Superscript II enzyme), 10 solution for a few seconds before they were flash frozen in liquid mmol/L of DTT, 200 units of Superscript II (Life Technologies, cat nitrogen. Diffraction data were collected at beam-line 19ID at 18064014), 0.5 mmol/L of dNTP mix (Promega, cat U1515), and Advanced Photon Source (Argonne National Laboratory). All data 40 mg/mL random hexamer primers (Roche, cat 11034731001) were indexed and scaled with program HKL2000 (21). Model using the following thermocycler program: 25C for 10 minutes, building and refinement were carried out with COOT (22) and 42C for 50 minutes, and then 72C for 10 minutes. A total of 1.25 REFMACS (23), respectively. mL of the resulting cDNA was used in each quantitative PCR reaction in A&B Applied Biosystem ViiA 7 equipment using Isothermal titration calorimetry SYBR Select Master Mix or TaqMan Mix supplied by A&B Human HIF2a-B was expressed and purified as described Applied Biosystem (cat 4472913). Each sample was run in trip- earlier (20). Rat HIF2a differs from human HIF2a-B by licate. The expression of specific genes was normalized against only three amino acids. So, the expression vector for human cyclophillin.
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