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).
KRAS
regulates many cellular processes including proliferation,
survival, and differentiation. Point mutants of KRAS have long been
known to be molecular drivers of cancer. KRAS p.G12C, which occurs in approximately 14% of lung adenocarcinomas, 3–5%
of colorectal cancers, and low levels in other solid tumors, represents
an attractive therapeutic target for covalent inhibitors. Herein,
we disclose the discovery of a class of novel, potent, and selective
covalent inhibitors of KRASG12C identified through a custom
library synthesis and screening platform called Chemotype Evolution
and structure-based design. Identification of a hidden surface groove
bordered by H95/Y96/Q99 side chains was key to the optimization of
this class of molecules. Best-in-series exemplars exhibit a rapid
covalent reaction with cysteine 12 of GDP-KRASG12C with
submicromolar inhibition of downstream signaling in a KRASG12C-specific manner.
A 10-step solid-supported, enantioselective synthesis suitable for the rapid preparation of large numbers of diverse structural analogues of saframycin A is described. The synthetic route, which bears analogy to solid-phase peptide synthesis, involves the directed condensation of N-protected alpha-amino aldehyde reactants. A novel dual linker was developed for attachment of intermediates to the solid support via a C-protective group, a substituted morpholino nitrile derivative. The route employs a novel diastereospecific cyclorelease mechanism, supports structural variation at multiple sites in the saframycin core, and obviates the need for chromatographic purification of the products or any intermediate. To demonstrate the feasibility of structural variation at multiple sites, a matrix of 16 saframycin A analogues was prepared by parallel synthesis with simultaneous variation of two sites. This work is notable not only as a preliminary step toward large-scale library construction but also as an example of the use of sequential stereoselective C-C bond-forming reactions on the solid phase for the preparation of natural product analogues.
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