KRASG12C has emerged as a promising target
in the treatment
of solid tumors. Covalent inhibitors targeting the mutant cysteine-12
residue have been shown to disrupt signaling by this long-“undruggable”
target; however clinically viable inhibitors have yet to be identified.
Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99)
we identified in KRASG12C to identify inhibitors suitable
for clinical development. Structure-based design efforts leading to
the identification of a novel quinazolinone scaffold are described,
along with optimization efforts that overcame a configurational stability
issue arising from restricted rotation about an axially chiral biaryl
bond. Biopharmaceutical optimization of the resulting leads culminated
in the identification of AMG 510, a highly potent, selective, and
well-tolerated KRASG12C inhibitor currently in phase I
clinical trials (NCT03600883).
β-Secretase inhibitors are potentially disease-modifying treatments for Alzheimer's disease. Previous efforts in our laboratory have resulted in hydroxyethylamine-derived inhibitors such as 1 with low nanomolar potency against β-site amyloid precursor protein cleaving enzyme (BACE). When dosed intravenously, compound 1 was also shown to significantly reduce Aβ40 levels in plasma, brain, and cerebral spinal fluid. Herein, we report further optimizations that led to the discovery of inhibitor 16 as a novel, potent, and orally efficacious BACE inhibitor.
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