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[2].IC50 & Target: IC50: 6 nM (HIF-2α)In Vitro: PT2399 (compound 10f) inhibits HIF-2α with an IC50 of 6 nM.
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].
In Vivo: PT2399 inhibits tumor cell proliferation 3.5 fold in renal cell carcinoma (RCC) bearing mice.
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 .
PT2399 directly inhibits HIF-2α causes tumor regression in preclinical models of primary and metastatic pVHL-defective ccRCC in an on-target fashion[2].