G protein coupled receptor 119 (GPR119) is viewed as an attractive target for the treatment of type 2 diabetes and other elements of the metabolic syndrome. During a program toward discovering agonists of GPR119, we herein describe optimization of an initial lead compound, 2, into a development candidate, 42. A key challenge in this program of work was the insolubility of the lead compound. Small-molecule crystallography was utilized to understand the intermolecular interactions in the solid state and resulted in a switch from an aryl sulphone to a 3-cyanopyridyl motif. The compound was shown to be effective in wild-type but not knockout animals, confirming that the biological effects were due to GPR119 agonism.
The RAS/MAPK pathway is a major driver of oncogenesis
and is dysregulated
in approximately 30% of human cancers, primarily by mutations in the
BRAF or RAS genes. The extracellular-signal-regulated kinases (ERK1
and ERK2) serve as central nodes within this pathway. The feasibility
of targeting the RAS/MAPK pathway has been demonstrated by the clinical
responses observed through the use of BRAF and MEK inhibitors in BRAF
V600E/K metastatic melanoma; however, resistance frequently develops.
Importantly, ERK1/2 inhibition may have clinical utility in overcoming
acquired resistance to RAF and MEK inhibitors, where RAS/MAPK pathway
reactivation has occurred, such as relapsed BRAF V600E/K melanoma.
We describe our structure-based design approach leading to the discovery
of AZD0364, a potent and selective inhibitor of ERK1 and ERK2. AZD0364
exhibits high cellular potency (IC50 = 6 nM) as well as
excellent physicochemical and absorption, distribution, metabolism,
and excretion (ADME) properties and has demonstrated encouraging antitumor
activity in preclinical models.
There are a number of small-molecule inhibitors targeting the RAS/RAF/MEK/ERK signaling pathway that have either been approved or are in clinical development for oncology across a range of disease indications. The inhibition of ERK1/2 is of significant current interest, as cell lines with acquired resistance to BRAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition in preclinical models. This article reports on our recent work to identify novel, potent, and selective reversible ERK1/2 inhibitors from a low-molecular-weight, modestly active, and highly promiscuous chemical start point, compound 4. To guide and inform the evolution of this series, inhibitor binding mode information from X-ray crystal structures was critical in the rapid exploration of this template to compound 35, which was active when tested in in vivo antitumor efficacy experiments.
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