XL388

XL388 is an orally bioavailable and ATP-competitive inhibitor of mammalian target of rapamycin (mTOR; IC₅₀ = 9.9 nM).¹ It is selective for mTOR over a panel of more than 140 kinases, including various PI3Ks (IC₅₀s = >3,000 nM). It inhibits mTOR complex 1 (mTORC1) and mTORC2 in vitro (IC₅₀s = 8 and 166 nM, respectively).² XL388 induces cytotoxicity in MG-63, U2OS, and Saos-2 osteosarcoma and 786-0 kidney cancer cells and increases apoptosis in 786-0 and MG-63 cells in a concentration-dependent manner.^3,4 It also induces cell cycle arrest at the G₁ phase and increases autophagy in MG-63 cells.³ XL388 (50 and 100 mg/kg) reduces tumor growth in an MCF-7 breast cancer mouse xenograft model and inhibits phosphorylation of the mTORC1 and mTORC2 substrates p70S6K, S6, 4E-BP1, and Akt in MCF-7 and PC-3 xenograft tumors when administered at a dose of 100 mg/kg.¹ XL388 (20 mg/kg) also reduces tumor growth in U2OS and 786-0 mouse xenograft models.^3,4

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1. Takeuchi, C.S., Kim, B.G., Blazey, C.M., et al. Discovery of a novel class of highly potent, selective, ATP-competitive, and orally bioavailable inhibitors of the mammalian target of rapamycin (mTOR). J. Med. Chem. 56(6), 2218-2234 (2013).

2. Miller, N. Abstract B146: XL388: A novel, selective, orally bioavailable mTORC1 and mTORC2 inhibitor that demonstrates pharmacodynamic and antitumor activity in multiple human cancer xenograft models. Mol. Cancer Ther. 8(Suppl 12), B146 (2009).

3. Zhu, Y.-R., Zhou, X.-z., Zhu, L.-q., et al. The anti-cancer activity of the mTORC1/2 dual inhibitor XL388 in preclinical osteosarcoma models. Oncotarget (2016).

4. Xiong, Z., Zang, Y., Zhong, S., et al. The preclinical assessment of XL388, a mTOR kinase inhibitor, as a promising anti-renal cell carcinoma agent. Oncotarget 8(18), 30151-30161 (2017).