WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 207004
CAS#: 1672668-24-4
Description: Belzutifan, also known as PT2977 and MK-6482, is HIF-2alpha inhibitor. PT2977 binds to and blocks the function of HIF-2alpha, thereby preventing HIF-2alpha heterodimerization and its subsequent binding to DNA. This results in decreased transcription and expression of HIF-2alpha downstream target genes, many of which regulate hypoxic signaling. This inhibits cell growth and survival of HIF-2alpha-expressing tumor cells. HIF-2alpha, the alpha subunit for the heterodimeric transcription factor HIF-2, is overexpressed in many cancers and promotes tumorigenesis. Belzutifan was approved in 2021 for treatment of von Hippel-Lindau disease under certain conditions
MedKoo Cat#: 207004
Name: Belzutifan
CAS#: 1672668-24-4
Chemical Formula: C17H12F3NO4S
Exact Mass: 383.0439
Molecular Weight: 383.3412
Elemental Analysis: C, 53.27; H, 3.16; F, 14.87; N, 3.65; O, 16.69; S, 8.36
Synonym: MK-6482; MK 6482; MK6482; PT2977; PT-2977; PT 2977; Belzutifan
IUPAC/Chemical Name: 3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile
InChi Key: LOMMPXLFBTZENJ-ZACQAIPSSA-N
InChi Code: InChI=1S/C17H12F3NO4S/c1-26(23,24)12-3-2-11(13-14(12)17(22)16(20)15(13)19)25-10-5-8(7-21)4-9(18)6-10/h2-6,15-17,22H,1H3/t15-,16-,17+/m1/s1
SMILES Code: N#CC1=CC(F)=CC(OC2=CC=C(S(=O)(C)=O)C3=C2[C@@H](F)[C@@H](F)[C@H]3O)=C1
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO
Shelf Life: >3 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
| Biological target: | Belzutifan (PT2977) is an orally active and selective HIF-2α inhibitor with an IC50 of 9 nM. |
| In vitro activity: | The complex structure shows that belzutifan binds into the PAS-B pocket of HIF-2α, and it destabilizes the dimerization of HIF-2α and ARNT through allosteric effects mainly mediated by the key residue M252 of HIF-2α near the dimer interface. This study further explored the inhibitory effects of belzutifan using biochemical and functional assays. The time-resolved fluorescence energy transfer (TR-FRET)-based binding assay showed that belzutifan disrupts the dimerization of HIF-2α and ARNT with a Ki value of 20 nM. The luciferase reporter assay indicated that belzutifan can efficiently inhibit the transcriptional activity of HIF-2α with an IC50 value of 17 nM. Besides, the real-time PCR assay illustrated that belzutifan can reduce the expression of HIF-2α downstream genes in 786-O kidney cancer cells in a dose-dependent manner. Reference: Mol Pharmacol. 2022 Sep 27:MOLPHARM-AR-2022-000525. https://pubmed.ncbi.nlm.nih.gov/36167425/ |
| In vivo activity: | TBD |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 50.0 | 130.43 |
The following data is based on the product molecular weight 383.3412 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | Ren X, Diao X, Zhuang J, Wu D. Structural basis for the allosteric inhibition of hypoxia-inducible factor (HIF)-2 by belzutifan. Mol Pharmacol. 2022 Sep 27:MOLPHARM-AR-2022-000525. doi: 10.1124/molpharm.122.000525. Epub ahead of print. PMID: 36167425. |
| In vitro protocol: | Ren X, Diao X, Zhuang J, Wu D. Structural basis for the allosteric inhibition of hypoxia-inducible factor (HIF)-2 by belzutifan. Mol Pharmacol. 2022 Sep 27:MOLPHARM-AR-2022-000525. doi: 10.1124/molpharm.122.000525. Epub ahead of print. PMID: 36167425. |
| In vivo protocol: | TBD |
1: Deeks ED. Belzutifan: First Approval. Drugs. 2021 Nov;81(16):1921-1927. doi: 10.1007/s40265-021-01606-x. PMID: 34613603.
2: Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan VK, Maughan BL, Oudard S, Else T, Maranchie JK, Welsh SJ, Thamake S, Park EK, Perini RF, Linehan WM, Srinivasan R; MK-6482-004 Investigators. Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease. N Engl J Med. 2021 Nov 25;385(22):2036-2046. doi: 10.1056/NEJMoa2103425. PMID: 34818478; PMCID: PMC9275515.
3: Visweswaran V, Pavithran K. Belzutifan: A Narrative Drug Review. Curr Drug Res Rev. 2022;14(2):88-95. doi: 10.2174/2589977514666220401094724. PMID: 35366789.
4: Choueiri TK, Bauer TM, Papadopoulos KP, Plimack ER, Merchan JR, McDermott DF, Michaelson MD, Appleman LJ, Thamake S, Perini RF, Zojwalla NJ, Jonasch E. Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat Med. 2021 May;27(5):802-805. doi: 10.1038/s41591-021-01324-7. Epub 2021 Apr 22. Erratum in: Nat Med. 2021 Oct;27(10):1849. PMID: 33888901; PMCID: PMC9128828.
5: Belzutifan. Am J Health Syst Pharm. 2021 Dec 9;78(24):2185-2187. doi: 10.1093/ajhp/zxab366. PMID: 34718390.
6: Fallah J, Brave MH, Weinstock C, Mehta GU, Bradford D, Gittleman H, Bloomquist EW, Charlab R, Hamed SS, Miller CP, Dorff SE, Chambers WA, Mixter BD, Dinin J, Pierce WF, Ricks TK, Tang S, Donoghue M, Pazdur R, Amiri-Kordestani L, Ibrahim A, Beaver JA. FDA Approval Summary: Belzutifan for von Hippel-Lindau Disease-Associated Tumors. Clin Cancer Res. 2022 Nov 14;28(22):4843-4848. doi: 10.1158/1078-0432.CCR-22-1054. PMID: 35727604; PMCID: PMC9669093.
7: Kamihara J, Hamilton KV, Pollard JA, Clinton CM, Madden JA, Lin J, Imamovic A, Wall CB, Wassner AJ, Weil BR, Heeney MM, Vargas SO, Kaelin WG Jr, Janeway KA, Perini RF, Zojwalla NJ, Voss SD, DuBois SG. Belzutifan, a Potent HIF2α Inhibitor, in the Pacak-Zhuang Syndrome. N Engl J Med. 2021 Nov 25;385(22):2059-2065. doi: 10.1056/NEJMoa2110051. PMID: 34818480.
8: Choi WW, Boland JL, Kalola A, Lin J. Belzutifan (MK-6482): Biology and Clinical Development in Solid Tumors. Curr Oncol Rep. 2023 Feb;25(2):123-129. doi: 10.1007/s11912-022-01354-5. Epub 2023 Jan 11. PMID: 36630072.
9: Romero D. Belzutifan is active in VHL-related cancers. Nat Rev Clin Oncol. 2022 Feb;19(2):72. doi: 10.1038/s41571-021-00587-w. PMID: 34893759.
10: McCabe EM, Lee S, Rasmussen TP. Belzutifan (Welireg™) for von Hippel Lindau disease. Trends Pharmacol Sci. 2022 Oct;43(10):882-883. doi: 10.1016/j.tips.2022.05.002. Epub 2022 Jun 9. PMID: 35691787.
11: Romero D. Belzutifan has potential in RCC. Nat Rev Clin Oncol. 2021 Jun;18(6):322. doi: 10.1038/s41571-021-00517-w. PMID: 33931768.
12: Cowman SJ, Koh MY. Revisiting the HIF switch in the tumor and its immune microenvironment. Trends Cancer. 2022 Jan;8(1):28-42. doi: 10.1016/j.trecan.2021.10.004. Epub 2021 Nov 4. PMID: 34743924; PMCID: PMC8702465.
13: Pelle E, Al-Toubah T, Morse B, Strosberg J. Belzutifan in a Patient With VHL-Associated Metastatic Pancreatic Neuroendocrine Tumor. J Natl Compr Canc Netw. 2022 Dec;20(12):1285-1287. doi: 10.6004/jnccn.2022.7047. PMID: 36509068.
14: Zhou J, Gong K. Belzutifan: a novel therapy for von Hippel-Lindau disease. Nat Rev Nephrol. 2022 Apr;18(4):205-206. doi: 10.1038/s41581-022-00544-5. PMID: 35132216.
15: Bensalah K, Khene ZE, Massard C. Re: Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease. Eur Urol. 2022 May;81(5):545-546. doi: 10.1016/j.eururo.2022.01.014. Epub 2022 Jan 31. PMID: 35094899.
16: Dhawan A, Peereboom DM, Stevens GH. First clinical experience with belzutifan in von Hippel-Lindau disease associated CNS hemangioblastoma. CNS Oncol. 2022 Jul 12;11(3):CNS91. doi: 10.2217/cns-2022-0008. Epub ahead of print. PMID: 35819008; PMCID: PMC9280404.
17: Wang K, Crona J, Beuschlein F, Grossman AB, Pacak K, Nölting S. Targeted Therapies in Pheochromocytoma and Paraganglioma. J Clin Endocrinol Metab. 2022 Nov 23;107(11):2963-2972. doi: 10.1210/clinem/dgac471. PMID: 35973976; PMCID: PMC9923802.
18: FDA OK's HIF2α Inhibitor Belzutifan. Cancer Discov. 2021 Oct;11(10):2360-2361. doi: 10.1158/2159-8290.CD-NB2021-0377. Epub 2021 Sep 3. PMID: 34479868.
19: Arevalo A, Patel N, Muraki P, Ohtake S, Bratslavsky G, Clark C, Mann J, Iliopoulos O, Jonasch E, Srinivasan R, Shuch B. Understanding the Impact of Belzutifan on Treatment Strategies for Patients with VHL. J Kidney Cancer VHL. 2022 Sep 28;9(3):41-46. doi: 10.15586/jkcvhl.v9i3.245. PMID: 36310638; PMCID: PMC9551368.
20: Motzer RJ, Schmidinger M, Eto M, Suarez C, Figlin R, Liu Y, Perini R, Zhang Y, Heng DY. LITESPARK-011: belzutifan plus lenvatinib vs cabozantinib in advanced renal cell carcinoma after anti-PD-1/PD-L1 therapy. Future Oncol. 2023 Jan;19(2):113-121. doi: 10.2217/fon-2022-0802. Epub 2023 Feb 8. PMID: 36752726.
