LY3023414

LY3023414 is a dual inhibitor of PI3K and mTOR.¹ It selectively inhibits PI3Kα, PI3Kβ, 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 β-glycerophosphate-, ascorbic acid-, and dexamethasone-induced osteoclast differentiation in MC3T3-E1 murine osteoblasts into osteoclasts at 160 µM.² 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.¹ LY3023414 (10 mg/kg twice per day) decreases tumor volume in a 786-O mouse xenograft model.

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1. Smith, M.C., Mader, M.M., Cook, J.A., et al. Characterization of LY3023414, a novel PI3K/mTOR dual inhibitor eliciting transient target modulation to impede tumor growth. Mol. Cancer Ther. 15(10), 2344-2356 (2016).

2. Chen, X., Chen, W., Aung, Z.M., et al. LY3023414 inhibits both osteogenesis and osteoclastogenesis through the PI3K/Akt/GSK3 signalling pathway. Bone Joint Res. 10(40, 237-249 (2021).