The DOI matches its Crossref record; 39 of the 40 references it cites were found in a registry or an index.
A Small-Molecule Antagonist of HIF2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma
Published version of a preprint
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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Recently, compounds designated PT2385 and PT2977 were shown to selectively block dimerization of HIF-2α with HIF-1β (44)”
From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [44]
In the citing paper
“Belzutifan and its predecessor PT2385 bind to a hydrophobic cavity within the PAS-B domain of HIF-2α, allosterically preventing heterodimerization with HIF-1β and formation of a transcriptionally active complex [410].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [410]
In the citing paper
“Indeed, recent studies have shown that HIF-2α can be targeted by selective inhibitors and have indicated that these molecules effectively suppress cancer cell growth and tumor angiogenesis characteristics in ccRCC79–82.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [80]
Citations
Cites
[20] Processing of X-ray diffraction data collected in oscillation mode
Otwinowski, Z., & Minor, W. (1997) · Methods in Enzymology · doi:10.1016/s0076-6879(97)76066-x · Cited by 33,475
Coot : model-building tools for molecular graphics
Emsley, P., & Cowtan, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904019158 · Cited by 30,571
NMRPipe: A multidimensional spectral processing system based on UNIX pipes
Delaglio, F., Grzesiek, S., Vuister, G. W., Zhu, G., Pfeifer, J., & Bax, A. (1995) · Journal of Biomolecular NMR · doi:10.1007/bf00197809 · Cited by 15,961
Refinement of Macromolecular Structures by the Maximum-Likelihood Method
Murshudov, G. N., Vagin, A. A., & Dodson, E. J. (1997) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444996012255 · Cited by 14,796
Wang, G. L., Jiang, B. H., Rue, E. A., & Semenza, G. L. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.12.5510 · Cited by 6,212
Jaakkola, P., Mole, D. R., Tian, Y.-M., Wilson, M. I., Gielbert, J., Gaskell, S. J., Kriegsheim, A. V., Hebestreit, H. F., Mukherji, M., Schofield, C. J., et al. (2001) · Science · doi:10.1126/science.1059796 · Cited by 5,535
Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.
Kaelin, W. G., & Ratcliffe, P. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.04.009 · Cited by 3,251
A conserved family of prolyl-4-hydroxylases that modify HIF
Bruick, R. K., & McKnight, S. L. (2001) · Science · doi:10.1126/science.1066373 · Cited by 2,549
Hypoxia-inducible factors and the response to hypoxic stress
Majmundar, A. J., Wong, W. J., & Simon, M. C. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.022 · Cited by 2,380
HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression
Keith, B., Johnson, R. S., & Simon, M. C. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3183 · Cited by 1,693
Cited by
Sorted by citations
Glutamine reliance in cell metabolism
Yoo, H. C., Yu, Y. C., Sung, Y., & Han, J. M. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-00504-8 · Cited by 1,021
Targeting renal cell carcinoma with a HIF-2 antagonist
Chen, W., Hill, H., Christie, A., Kim, M. S., Holloman, E., Pavia-Jimenez, A., Homayoun, F., Ma, Y., Patel, N., Yell, P., et al. (2016) · Nature · doi:10.1038/nature19796 · Cited by 709
Self-citationHypoxia-inducible factors: cancer progression and clinical translation
Wicks, E. E., & Semenza, G. L. (2022) · Journal of Clinical Investigation · doi:10.1172/jci159839 · Cited by 626
Targeting the HIF2–VEGF axis in renal cell carcinoma
Choueiri, T. K., & Kaelin, W. G. (2020) · Nature Medicine · doi:10.1038/s41591-020-1093-z · Cited by 477
On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models
Cho, H., Du, X., Rizzi, J. P., Liberzon, E., Chakraborty, A. A., Gao, W., Carvo, I., Signoretti, S., Bruick, R. K., Josey, J. A., et al. (2016) · Nature · doi:10.1038/nature19795 · Cited by 451
Self-citation
Metadata
- Authors
- 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.
- Affiliations
- Peloton Therapeutics, Inc., Dallas, Texas.
- Corresponding author
- Wallace, Eli M.
- ORCID
- Venue
- Cancer Research
- Published
- 2016-09-15
- Volume
- 76
- Issue
- 18
- Pages
- 5491-5500
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2514212469
- Cited by
- 336
- References
- 40
- Citations by year
- 2026: 27 · 2025: 34 · 2024: 38 · 2023: 36 · 2022: 25 · 2021: 37 · 2020: 41 · 2019: 38 · 2018: 30 · 2017: 22 · 2016: 7
- FWCI
- 13.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Renal cell carcinoma treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- HIF-2α, PT2385, clear cell renal cell carcinoma, small molecule inhibitors, hypoxia-inducible factor, VEGF-A, plasminogen activator inhibitor-1, cyclin D1, tumor xenografts, oral anticancer therapy, cardiovascular safety
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Antineoplastic Agents, Calorimetry, Carcinoma, Renal Cell, Humans, Immunohistochemistry, Kidney Neoplasms, Polymerase Chain Reaction, Mice, SCID, Crystallography, X-Ray, Xenograft Model Antitumor Assays, Cell Line, Tumor, Immunoprecipitation, Mice, Basic Helix-Loop-Helix Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
