Sunday, November 29, 2015

Drugs in Clinical Pipeline: Apitolisib

Apitolisib [(S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one] is a selective, potent, orally bioavailable inhibitor of Class I PI3 kinase (PI3K) and mTOR kinase (TORC1/2) with excellent pharmacokinetic and pharmaceutical properties. Apitolisib displayed excellent potency against class I PI3K isoforms (IC50 PI3K-αβδ and γ = 4.8, 27, 6.7 and 14 nM) and mTOR kinase (IC50 = 17 nM) and selectivity against a large panel of other kinases, including closely related PIKK family members DNA-PK (Ki = 623 nM), VPS34 (IC50 = 2000 nM), c2alpha (IC50 = 1300 nM), and c2beta (IC50 = 794 nM) [1, 2].

1. Sutherlin, D. P.; et. al. Discovery of a potent, selective, and orally available class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer. J Med Chem 2011, 54(21), 7579-7587.
2. Wallin, J. J.; et. al. GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway. Mol Cancer Ther 2011, 10(12), 2426-2436.