CH5132799

CH5132799, also known as PA-799, is a novel class I PI3K inhibitor, which exhibited a strong inhibitory activity especially against PI3Kα (IC (50) =0.014 μM) . In human tumor cell lines with PI3K pathway activation, CH5132799 showed potent antiproliferative activity. CH5132799 is orally available and showed significant antitumor activity in PI3K pathway-activated human cancer xenograft models in mice. CH5132799 selectively inhibited class I PI3Ks and PI3Kα mutants in in vitro kinase assays. Tumors harboring PIK3CA mutations were significantly sensitive to CH5132799 in vitro and were remarkably regressed by CH5132799 in in vivo mouse xenograft models. (In Vitro) :Izorlisib (CH5132799) is a selective class I PI3K inhibitor with potent antitumor activity against tumors harboring the PIK3CA mutations. Izorlisib selectively inhibits class I PI3Ks and PI3Kα mutants in in vitro kinase assays. Izorlisib inhibits class I PI3Ks, particularly PI3Kα, with an IC50 of 14 nM. IC50 values against class II PI3Ks (C2α and C2β), a class III PI3K (Vps34), and a class IV PI3K (mTOR) are more than 100-fold higher than that against PI3Kα. Interestingly, slightly lower IC50 values are observed against PI3Kα with oncogenic mutations E542K, E545K, and H1047R than against wild-type (WT) PI3Kα. In an analysis of cocrystal structure with PI3Kγ (PBD ID: 3APC), Izorlisib is shown to interact with ATP-binding sites of the enzyme, suggesting an ATP competitive mode of inhibition. No significant inhibitory activities of Izorlisib are observed against a representative panel of 26 protein kinases, including RTKs, nonreceptor tyrosine kinases, and serine/threonine kinases. These data indicate that Izorlisib is a selective class I PI3K inhibitor, especially against PI3Kα and its mutants. Izorlisib shows superior antiproliferative activity across the 4 tumor types, with 75% (45/60) of lines having an IC50 below 1 μM and 38% (23/60) of lines having an IC50 below 0.3 μM. (In Vivo) :Mice bearing BT-474 tumors (n=14) are orally administered 50 mg/kg of Everolimus on a daily basis for 31 days and then randomized. After randomization, the mice are orally administered 50 mg/kg of Everolimus (n=4) and 12.5 mg/kg (n=5), and 25 mg/kg (n=5) of Izorlisib on a daily basis for 7 days. C, the vehicle-, Everolimus, and CH5132799-treated (25 mg/kg) tumors are resected at 4 hours after terminal administration in B, lysed, and analyzed by Western blotting. Izorlisib administration leads to a remarkable regression in a dose-dependent manner of the tumors regrown after the long-term Everolimus treatment. The tumors are resected at the end of treatment and analyzed by Western blotting with respect to PI3K pathway inhibition. Izorlisib suppresses various effectors in the PI3K pathway, including Akt, FoxO1, S6K, S6, and 4E-BP1, whereas Everolimus inhibits only phosphorylation of S6K and S6, both downstream effectors of mTORC1.