Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: The discovery of AZD8055 and AZD2014

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Abstract

The optimization of a potent and highly selective series of dual mTORC1 and mTORC2 inhibitors is described. An initial focus on improving cellular potency whilst maintaining or improving other key parameters, such as aqueous solubility and margins over hERG IC50, led to the discovery of the clinical candidate AZD8055 (14). Further optimization, particularly aimed at reducing the rate of metabolism in human hepatocyte incubations, resulted in the discovery of the clinical candidate AZD2014 (21).

Graphical abstract

The optimization of a novel series of highly potent and selective dual inhibitors of mTORC1 and mTORC2 is described culminating in the discovery of clinical candidates AZD8055 (14) and AZD2014 (21).

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Acknowledgments

The authors would like to thank Christine Chresta and Tom Harding for their help in preparing the biological data presented and Dr. Kin Tam for his help preparing the physicochemical data presented.

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