PT2399 is a first-in-class, orally available, small molecule inhibitor of HIF-2 that selectively disrupts the heterodimerization of HIF-2α with HIF-1β. PT2399 displays potent antitumor activity in vivo

HIF2α:6 nM

PT2399, a selective HIF-2 antagonist that was identified using a structure-based design approach. PT2399 dissociated HIF-2 (an obligatory heterodimer of HIF-2α-HIF-1β) in human ccRCC cells and suppressed tumorigenesis in 56% (10 out of 18) of such lines[1].PT2399 inhibits HIF-2α (IC50: 6 nM). PT2399 represses various HIF target genes in 786-O VHL / ccRCC cells, does not suppress HIF-1α-specific targets such as BNIP3. PT2399 can cripple HIF-2α’s ability to bind to Aryl hydrocarbon receptor nuclear translocator (ARNT). PT2399 (20 μM) induces off-target toxicity because it inhibits the proliferation of HIF-2α / 786-O cells and other cancer cell lines with undetectable HIF-2α. PT2399 (0.2–2 μM; 0-21 days) inhibits 786-O cells soft agar growth[2][3].

PT2399) that directly inhibits HIF-2α causes tumour regression in preclinical mouse models of primary and metastatic pVHL-defective clear cell renal cell carcinoma in an on-target fashion[2].PT2399 inhibits tumor cell proliferation 3.5 fold in renal cell carcinoma (RCC) bearing mice.PT2399 directly inhibits HIF-2α causes tumor regression in preclinical models of primary and metastatic pVHL-defective ccRCC in an on-target fashion.PT2399 reduces tumor cell density and increases fibrosis in RCC bearing mice.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][2].