LY3023414

LY3023414 is a dual inhibitor of PI3K and mTOR. It selectively inhibits PI3Kalpha, PI3Kbeta, and mTOR (IC50 = 83, 600, and 16 nM, respectively) over 283 other kinases at 20 µM but does inhibit DNA-dependent protein kinase (DNA-PK), ataxia-telangiectasia mutated kinase (ATM), the PI3K-related kinase SMG1, and ataxia-telangiectasia and Rad3-related protein/kinase (ATR, IC50s = 9.3, 160, 180, and 390 nM, respectively). LY3023414 decreases levels of phosphorylated Akt and 4E-BP1, indicating inhibition of PI3K and mTOR, respectively, in U87MG glioblastoma cells (IC50s = 106 and 187 nM, respectively). It also reduces the proliferation of primary mouse bone marrow-derived macrophages (BMDMs) when used at a concentration of 75 µM and decreases beta-glycerophosphate-, ascorbic acid-, and dexamethasone-induced osteoclast differentiation in MC3T3-E1 murine osteoblasts into osteoclasts at 160 µM. LY3023414 reduces proliferation in a panel of 31 cancer cell lines (IC50s = <0.122-1 µM) and induces cell cycle arrest at the G1 phase in 786-O renal carcinoma, H1975 non-small cell lung cancer (NSCLC), and A2780 ovarian cancer cells. LY3023414 (10 mg/kg twice per day) decreases tumor volume in a 786-O mouse xenograft model. InChI: InChI=1S/C23H26N4O3/c1-14(30-5)13-27-21-18-9-15(16-8-17(11-24-10-16)23(2,3)29)6-7-19(18)25-12-20(21)26(4)22(27)28/h6-12,14,29H,13H2,1-5H3/t14-/m0/s1 InChIKey: ACCFLVVUVBJNGT-AWEZNQCLSA-N SMILES: C[C@@H](CN1C2=C(N(C1=O)C)C=NC3=CC=C(C4=CN=CC(C(C)(O)C)=C4)C=C23)OC