Discovery and biological activity of a novel class I PI3K inhibitor, CH5132799.
PubMed PMID: 21558396.Ĥ: Ohwada J, Ebiike H, Kawada H, Tsukazaki M, Nakamura M, Miyazaki T, Morikami K, Yoshinari K, Yoshida M, Kondoh O, Kuramoto S, Ogawa K, Aoki Y, Shimma N. The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations. PubMed PMID: 25231405 PubMed Central PMCID: PMC4254850.ģ: Tanaka H, Yoshida M, Tanimura H, Fujii T, Sakata K, Tachibana Y, Ohwada J, Ebiike H, Kuramoto S, Morita K, Yoshimura Y, Yamazaki T, Ishii N, Kondoh O, Aoki Y. First-in-human study of CH5132799, an oral class I PI3K inhibitor, studying toxicity, pharmacokinetics, and pharmacodynamics, in patients with metastatic cancer. PubMed PMID: 25646183.Ģ: Blagden S, Omlin A, Josephs D, Stavraka C, Zivi A, Pinato DJ, Anthoney A, Decordova S, Swales K, Riisnaes R, Pope L, Noguchi K, Shiokawa R, Inatani M, Prince J, Jones K, Twelves C, Spicer J, Banerji U. CH5132799 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.ġ: Correction: First-in-Human Study of CH5132799, an Oral Class I PI3K Inhibitor, Studying Toxicity, Pharmacokinetics, and Pharmacodynamics, in Patients with Metastatic Cancer. The tumors are resected at the end of treatment and analyzed by Western blotting with respect to PI3K pathway inhibition. CH5132799 administration leads to a remarkable regression in a dose-dependent manner of the tumors regrown after the long-term Everolimus treatment. 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. 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 CH5132799 on a daily basis for 7 days.
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. CH5132799 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. These data indicate that CH5132799 is a selective class I PI3K inhibitor, especially against PI3Kα and its mutants. No significant inhibitory activities of CH5132799 are observed against a representative panel of 26 protein kinases, including RTKs, nonreceptor tyrosine kinases, and serine/threonine kinases. In an analysis of cocrystal structure with PI3Kγ (PBD ID: 3APC), CH5132799 is shown to interact with ATP-binding sites of the enzyme, suggesting an ATP competitive mode of inhibition. Interestingly, slightly lower IC50 values are observed against PI3Kα with oncogenic mutations E542K, E545K, and H1047R than against wild-type (WT) PI3Kα. 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. CH5132799 inhibits class I PI3Ks, particularly PI3Kα, with an IC50 of 14 nM. CH5132799 selectively inhibits class I PI3Ks and PI3Kα mutants in in vitro kinase assays. CH5132799 inhibits class I PI3Ks, particularly PI3Kα, with an IC50 of 14 nM.ĬH5132799 is a selective class I PI3K inhibitor with potent antitumor activity against tumors harboring the PIK3CA mutations. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.ĭry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).Ġ - 4 C for short term (days to weeks), or -20 C for long term (months).ĬH5132799 is a selective class I PI3K inhibitor. Shipped under ambient temperature as non-hazardous chemical. >98% (or refer to the Certificate of Analysis)
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