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This article presents the journey to belzutifan and subsequent developments.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We discuss the structure\u2010based design leading to the first\u2010in\u2010human drug, PT2385, as well as subsequent modifications to improve pharmacokinetic properties leading to PT2977\/belzutifan. Detailed analyses are presented of key HIF\u20102\u03b1 structural features, the mechanism of drug action, and how this family of drugs performed in preclinical models. Belzutifan\u2019s impact on patients with VHL syndrome, sporadic advanced ccRCC and pheochromocytoma\/paraganglioma is discussed, three areas where belzutifan has obtained Food and Drug Administration approval. Drug combination strategies, mechanisms of resistance, and emerging strategies to overcome them, including siRNA\u2010based therapeutics, are presented. Alternative HIF\u20102\u03b1 inhibitors are examined, including NKT2152 and AB521.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>By expanding upon the foundation established by belzutifan, the field is poised for further therapeutic advances.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cncr.70239","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T15:32:23Z","timestamp":1770132743000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Targeting HIF\u20102\u03b1 in renal cell carcinoma: Expanding upon belzutifan"],"prefix":"10.1002","volume":"132","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5250-7810","authenticated-orcid":false,"given":"Melanie","family":"Rodriguez","sequence":"first","affiliation":[{"name":"Department of Biochemistry The University of Texas Southwestern Medical Center at Dallas  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Division of Hematology\u2010Oncology The University of Texas Southwestern Medical Center at Dallas  Dallas Texas USA"},{"name":"Kidney Cancer Program Simmons Comprehensive Cancer Center The University of Texas Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5659-5355","authenticated-orcid":false,"given":"Uttam K.","family":"Tambar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry The University of Texas Southwestern Medical Center at Dallas  Dallas Texas USA"},{"name":"Kidney Cancer Program Simmons Comprehensive Cancer Center The University of Texas Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Brugarolas","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Division of Hematology\u2010Oncology The University of Texas Southwestern Medical Center at Dallas  Dallas Texas USA"},{"name":"Kidney Cancer Program Simmons Comprehensive Cancer Center The University of Texas Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,3]]},"reference":[{"key":"e_1_2_11_2_1","volume-title":"International Agency for Research on Cancer","author":"Global Cancer Observatory"},{"key":"e_1_2_11_3_1","volume-title":"Cancer Stat Facts: Kidney and Renal Pelvis Cancer [Internet]","year":"2025"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2018.79.1905"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/medsci12010012"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12222"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41581\u2010020\u201000359\u20102"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.02.020"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/ppo.0000000000000480"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.can\u201013\u20100360"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09639"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2323"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1470\u20102045(12)70584\u20103"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.cd\u201017\u20100292"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2015.123"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.03.043"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/332268a0"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.8493574"},{"key":"e_1_2_11_19_1","unstructured":"Foundation TN.Nobel Prize Outreach.2025. 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