We describe our discovery and development
of potent and highly
selective inhibitors of human constitutive proteasome chymotryptic
activity (β5c). Structure–activity relationship studies
of the novel class of inhibitors focused on optimization of N-cap, C-cap, and side chain of the chemophore
asparagine. Compound 32 is the most potent and selective
β5c inhibitor in this study. A docking study provides a structure
rationale for potency and selectivity. Kinetic studies show a reversible
and noncompetitive inhibition mechanism. It enters the cells to engage
the proteasome target, potently and selectively kills multiple myeloma
cells, and does so by synergizing with a β5i-selective inhibitor.
A novel series of imidazo[4,5-c]pyridine-based CDK2 inhibitors were designed from the structure of CYC202 via scaffold hopping strategy. These compounds were synthesized and biologically evaluated for their CDK2 inhibitory and in vitro anti-proliferation potential against cancer cell lines. Several compounds exhibited potent CDK2 inhibition with IC values of less than 1 µM. The most potent compound 5b showed excellent CDK2 inhibitory (IC = 21 nM) and in vitro anti-proliferation activity against three different cell lines (HL60, A549, and HCT116). The molecular docking and dynamic studies portrayed the potential binding mechanism between 5b and CDK2, and several key interactions between them were observed, which would be the reason for its potent CDK2 inhibitory and anti-proliferation activities. Therefore, the pyridin-3-ylmethyl moiety would serve as an excellent pharmacophore for the development of novel CDK2 inhibitors for targeted anti-cancer therapy.
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