Attempts to directly
drug the important oncogene KRAS have met
with limited success despite numerous efforts across industry and
academia. The KRASG12C mutant represents an “Achilles
heel” and has recently yielded to covalent targeting with small
molecules that bind the mutant cysteine and create an allosteric pocket
on GDP-bound RAS, locking it in an inactive state. A weak inhibitor
at this site was optimized through conformational locking of a piperazine–quinazoline
motif and linker modification. Subsequent introduction of a key methyl
group to the piperazine resulted in enhancements in potency, permeability,
clearance, and reactivity, leading to identification of a potent KRASG12C inhibitor with high selectivity and excellent cross-species
pharmacokinetic parameters and in vivo efficacy.
Crystals extracted from human osteoarthritic knee cartilage induce the production of proinflammatory and catabolic mediators (NO, MMP-13 and PGE(2)) in human primary chondrocytes and synoviocytes. Synthetic calcium phosphate and pyrophosphate crystals elicit a similar response in those cells. Our findings suggest that these crystals could contribute to cartilage degradation and synovitis in OA.
KRAS is an archetypal high-value
intractable oncology drug target.
The glycine to cysteine mutation at codon 12 represents an Achilles
heel that has now rendered this important GTPase druggable. Herein,
we report our structure-based drug design approach that led to the
identification of 21, AZD4625, a clinical development
candidate for the treatment of KRASG12C positive tumors.
Highlights include a quinazoline tethering strategy to lock out a
bio-relevant binding conformation and an optimization strategy focused
on the reduction of extrahepatic clearance mechanisms seen in preclinical
species. Crystallographic analysis was also key in helping to rationalize
unusual structure–activity relationship in terms of ring size
and enantio-preference. AZD4625 is a highly potent and selective inhibitor
of KRASG12C with an anticipated low clearance and high
oral bioavailability profile in humans.
Inhibition
of Mer and Axl kinases has been implicated as a potential
way to improve the efficacy of current immuno-oncology therapeutics
by restoring the innate immune response in the tumor microenvironment.
Highly selective dual Mer/Axl kinase inhibitors are required to validate
this hypothesis. Starting from hits from a DNA-encoded library screen,
we optimized an imidazo[1,2-a]pyridine series using
structure-based compound design to improve potency and reduce lipophilicity,
resulting in a highly selective in vivo probe compound 32. We demonstrated dose-dependent in vivo efficacy and target engagement in Mer- and Axl-dependent efficacy
models using two structurally differentiated and selective dual Mer/Axl
inhibitors. Additionally, in vivo efficacy was observed
in a preclinical MC38 immuno-oncology model in combination with anti-PD1
antibodies and ionizing radiation.
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