PT2399 is a potent and selective HIF-2α antagonist, which directly binds to HIF-2α PAS B domain with an IC50 of 6 nM. PT2399 displays potent antitumor activity in vivo[1][2][3].

PT2399 (compound 10f) inhibits HIF-2α with an IC50 of 6 nM[3]. PT2399 can bind directly to the HIF-2α PAS B domain, and cripple HIF-2α's ability to bind to Aryl hydrocarbon receptor nuclear translocator (ARNT)[2].PT2399 (20 μM) causes off-target toxicity because it inhibits the proliferation of HIF-2α -/- 786-O cells and other cancer cell lines with undetectable HIF-2α[2]. PT2399 (0.2-2 μM; 0-21 days) inhibits 786-O cells soft agar growth[2].PT2399 represses various HIF target genes in 786-O VHL-/- ccRCC cells, does not suppress HIF-1α-specific targets such as BNIP3[2].

PT2399 inhibits tumor cell proliferation 3.5 fold in renal cell carcinoma (RCC) bearing mice[1].PT2399 reduces tumor cell density and increases fibrosis in RCC bearing mice[1].PT2399 (100 mg/kg; oral gavage; every 12 hours) is more active than SU 11248, and inhibits tumor growth in several SU 11248-resistant tumors in RCC bearing mice [1].PT2399 directly inhibits HIF-2α causes tumor regression in preclinical models of primary and metastatic pVHL-defective ccRCC in an on-target fashion[2].

[1]. Chen W, et al. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature. 2016 Nov 3;539(7627):112-117.
[2]. Cho H, et al. On-Target Efficacy of a HIF2α Antagonist in Preclinical Kidney Cancer Models. Nature. Nature. 2016 Nov 3;539(7627):107-111.
[3]. Wehn PM, et al. Design and Activity of Specific Hypoxia-Inducible Factor-2α (HIF-2α) Inhibitors for the Treatment of Clear Cell Renal Cell Carcinoma: Discovery of Clinical Candidate (S)-3-((2,2-Difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1 H-inden-4-yl)oxy)-5-fluorobenzonitrile (PT2385). J Med Chem. 2018 Nov 8;61(21):9691-9721.