Inhibitors of ataxia telangiectasia and Rad-3 related protein (ATR) could be useful as cancer therapeutics either as chemosensitizers in combination regimens with DNA damaging agents or potentially as single agent treatments in patients with mutations in other nodes of the DNA damage repair pathway. A saturation strategy was employed to improve both the physicochemical properties and selectivity of an ATR inhibitor HTS hit, while the use of PI3Kα mutants as ATR crystal structure surrogates enabled structure-based design to optimize potency. The resulting tetrahydropyrazolo[1,5-a]pyrazines (THPP) were potent, selective inhibitors of ATR which also displayed time-dependent inhibition (TDI) of CYP3A4. Trapping experiments were used to distinguish between two modes of reactive metabolite formation, and systematic deuteration of the THPP core probed the exact location of reactive metabolite formation and redirected their formation elsewhere in the molecule. Overall, these efforts illustrate SBDD towards ATR and the value of deuterium as a hydrogen bioisostere in cases of metabolic activation.

ATR inhibitors for cancer: SBDD and mitigation of TDI

252nd National Meeting (2016)

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