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MedKoo CAT#: 205747
Description: 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.
MedKoo Cat#: 205747
Name: CH5132799 (PA-799)
Chemical Formula: C15H19N7O3S
Exact Mass: 377.12701
Molecular Weight: 377.42146
Elemental Analysis: C, 47.73; H, 5.07; N, 25.98; O, 12.72; S, 8.50
Synonym: CH5132799; CH-5132799; CH 5132799; PA-799; PA799; PA-799.
IUPAC/Chemical Name: 5-(7-(methylsulfonyl)-2-morpholino-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrimidin-2-amine
InChi Key: JEGHXKRHKHPBJD-UHFFFAOYSA-N
InChi Code: InChI=1S/C15H19N7O3S/c1-26(23,24)22-3-2-11-12(10-8-17-14(16)18-9-10)19-15(20-13(11)22)21-4-6-25-7-5-21/h8-9H,2-7H2,1H3,(H2,16,17,18)
SMILES Code: NC1=NC=C(C2=C3C(N(S(=O)(C)=O)CC3)=NC(N4CCOCC4)=N2)C=N1
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 combination with trastuzumab, tumors disappeared in the trastuzumab-insensitive breast cancer model with the PIK3CA mutation. Moreover, CH5132799 did not reverse a negative feedback loop of PI3K/Akt/mTOR signaling and induced regression against tumors regrown after long-term mTORC1 inhibitor treatment. CONCLUSIONS: CH5132799 is a selective class I PI3K inhibitor with potent antitumor activity against tumors harboring the PIK3CA mutations. Prediction of CH5132799 response on the basis of PIK3CA mutations could enable patient stratification in clinical settings. (source: Clin Cancer Res. 2011 May 15;17(10):3272-81).
1: Correction: First-in-Human Study of CH5132799, an Oral Class I PI3K Inhibitor, Studying Toxicity, Pharmacokinetics, and Pharmacodynamics, in Patients with Metastatic Cancer. Clin Cancer Res. 2015 Feb 1;21(3):660. doi: 10.1158/1078-0432.CCR-14-3188. PubMed PMID: 25646183.
2: 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. First-in-human study of CH5132799, an oral class I PI3K inhibitor, studying toxicity, pharmacokinetics, and pharmacodynamics, in patients with metastatic cancer. Clin Cancer Res. 2014 Dec 1;20(23):5908-17. doi: 10.1158/1078-0432.CCR-14-1315. Epub 2014 Sep 17. Erratum in: Clin Cancer Res. 2015 Feb 1;21(3):660. Olmin, Aurelius [corrected to Omlin, Aurelius]. PubMed PMID: 25231405; PubMed Central PMCID: PMC4254850.
3: 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. The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations. Clin Cancer Res. 2011 May 15;17(10):3272-81. doi: 10.1158/1078-0432.CCR-10-2882. Epub 2011 May 10. PubMed PMID: 21558396.
4: 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. Discovery and biological activity of a novel class I PI3K inhibitor, CH5132799. Bioorg Med Chem Lett. 2011 Mar 15;21(6):1767-72. doi: 10.1016/j.bmcl.2011.01.065. Epub 2011 Jan 22. PubMed PMID: 21316229.