Upregulation of the fibroblast growth factor receptor
(FGFR) signaling
pathway has been implicated in multiple cancer types, including cholangiocarcinoma
and bladder cancer. Consequently, small molecule inhibition of FGFR
has emerged as a promising therapy for patients suffering from these
diseases. First-generation pan-FGFR inhibitors, while highly effective,
suffer from several drawbacks. These include treatment-related hyperphosphatemia
and significant loss of potency for the mutant kinases. Herein, we
present the discovery and optimization of novel FGFR2/3 inhibitors
that largely maintain potency for the common gatekeeper mutants and
have excellent selectivity over FGFR1. A combination of meticulous
structure–activity relationship (SAR) analysis, structure-based
drug design, and medicinal chemistry rationale ultimately led to compound 29, a potent and selective FGFR2/3 inhibitor with excellent in vitro absorption, distribution, metabolism, excretion
(ADME), and pharmacokinetics in rat. A pharmacodynamic study of a
closely related compound established that maximum inhibition of downstream
ERK phosphorylation could be achieved with no significant effect on
serum phosphate levels relative to vehicle.
Fibroblast growth factor receptors (FGFRs) are transmembrane receptor tyrosine kinases that regulate multiple physiological processes. Aberrant activation of FGFR2 and FGFR3 has been linked to the pathogenesis of many tumor types, including cholangiocarcinoma and bladder cancer. Current therapies targeting the FGFR2/3 pathway exploiting small-molecule kinase inhibitors are associated with adverse events due to undesirable inhibition of FGFR1 and FGFR4. Isoform-specific FGFR2 and FGFR3 inhibitors that spare FGFR1 and FGFR4 could offer a favorable toxicity profile and improved therapeutic window to current treatments. Herein we disclose the discovery of dual FGFR2/FGFR3 inhibitors exploiting scaffold repurposing of a previously reported ALK2 tool compound. Structure-based drug design and structure−activity relationship studies were employed to identify selective and orally bioavailable inhibitors with equipotent activity toward wild-type kinases and a clinically observed gatekeeper mutant.
Herein we report the discovery of a novel biaryl amide
series as
selective inhibitors of hematopoietic protein kinase 1 (HPK1). Structure–activity
relationship development, aided by molecular modeling, identified
indazole 5b as a core for further exploration because
of its outstanding enzymatic and cellular potency coupled with encouraging
kinome selectivity. Late-stage manipulation of the right-hand aryl
and amine moieties surmounted issues of selectivity over TRKA, MAP4K2,
and STK4 as well as generating compounds with balanced in
vitro ADME profiles and promising pharmacokinetics.
In spite of the great success of immune checkpoint inhibitors
in
immune-oncology therapy, an urgent need still exists to identify alternative
approaches to broaden the scope of therapeutic coverage. Hematopoietic
progenitor kinase 1 (HPK1), also known as MAP4K1, functions as a negative
regulator of activation signals generated by the T cell antigen receptor.
Herein we report the discovery of novel pyrazolopyridine derivatives
as selective inhibitors of HPK1. The structure–activity relationship
campaign led to the discovery of compound 16, which has
shown promising enzymatic and cellular potency with encouraging kinome
selectivity. The outstanding pharmacokinetic profiles of 16 in rats and monkeys supported further evaluations of its efficacy
and safety in preclinical models.
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