Design, synthesis and biological evaluation of thienopyridinones as Chk1 inhibitors

Versatile mechanisms of 2-substituted benzimidazoles in targeted cancer therapy

“…Most of them exhibited moderate to good Chk1 inhibitory activities. Among them, compounds 64a-c showed significant Chk1 inhibitory activities with IC 50 values of 4.05, 6.23, and 2.33 nM, respectively [119]. Some 2-substituted benzimidazoles were reported by Ni et al as a novel class of small molecule ChK-1 inhibitors.…”

Adventures in Scaffold Morphing: Discovery of Fused Ring Heterocyclic Checkpoint Kinase 1 (CHK1) Inhibitors

“…tert-Butyl (3S)-3-[(2-Bromo-4-cyanothieno[2,3-c]pyridin-7yl)amino]piperidine-1-carboxylate (11). To a solution of 2bromo-7-chlorothieno[2,3-c]pyridine-4-carbonitrile (2.80 g, 10.2 mmol) in N-methylpyrrolidine (NMP, 10.0 mL) were added potassium carbonate (4.23 g, 30.6 mmol) and tert-butyl (3S)-3aminopiperidine-1-carboxylate (4.92 g, 24.6 mmol).…”

“…The resulting solid was filtered and vacuum-dried to afford the title compound. 1 (11,428 mgs, 0.979 mmol) were added cesium carbonate (957 mg, 2.94 mmol), 3-fluorophenylboronic acid (206 mgs, 1.47 mmol), Pd(PPh 3 ) 4 (113 mgs, 0.0979 mmol), and dioxane/water (4 mL/2 mL). The reaction was heated to 80 °C for 1 h whereupon the reaction was cooled to rt, filtered, and purified using silica gel chromatography (100% hexanes to 100% ethyl acetate) to afford the title compound (241 mg, 54% yield).…”

“…CHK2 is activated by phosphorylation on Thr-68 mediated by ATM kinase in response to DNA damage and causes cell cycle arrest at the G1 phase. A CHK1 inhibitor would allow a cell with damaged DNA to abrogate the cell cycle arrest and progress through the cell cycle, ultimately leading to mitotic catastrophe and/or apoptosis. , CHK1 inhibitors have attracted substantial interest from both academia and industry as potential cancer therapeutics, and a number of diverse CHK1 inhibitors have been disclosed and evaluated in human clinical trials. − We previously reported two series of structurally distinct CHK1 inhibitors, thiophene carboxamide ureas (TCUs) and triazoloquinolones (TZQs) (Figure ). Our past efforts identified the clinical candidate 1 (AZD7762), a small molecule agent that could be dosed intravenously in combination with standard chemo- or radiotherapies and selectively sensitize p53-negative tumors over normal cells. − Herein, we report on our expanded medicinal chemistry exploration of CHK1 inhibitors and discovery of two new series of thienopyridine and indole carboxamide bicyclic CHK1 inhibitors, derived from X-ray structure-based modification or “scaffold morphing” of the TCU and TZQ chemical series.…”