Discovery and optimization of potent and selective imidazopyridine and imidazopyridazine mTOR inhibitors

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Abstract

mTOR is a critical regulator of cellular signaling downstream of multiple growth factors. The mTOR/PI3K/AKT pathway is frequently mutated in human cancers and is thus an important oncology target. Herein we report the evolution of our program to discover ATP-competitive mTOR inhibitors that demonstrate improved pharmacokinetic properties and selectivity compared to our previous leads. Through targeted SAR and structure-guided design, new imidazopyridine and imidazopyridazine scaffolds were identified that demonstrated superior inhibition of mTOR in cellular assays, selectivity over the closely related PIKK family and improved in vivo clearance over our previously reported benzimidazole series.

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Acknowledgments

The authors would like to acknowledge Wei Hu, Tisha San Miguel, and Leeanne Zalameda for enzyme and cell assay support. We are also grateful to Loren Berry, Xuhai Be, Liyue Huang, Meghan Langley, and Jonothan Roberts for PKDM support. Thanks to Pete Yakowec and Jin Tang for PI3Kγ expression and purification as well as Huilin Zhao and Linda Epstein for mTOR expression and purification.

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