2-Aminomethylthieno[3,2-d]pyrimidin-4(3H)-ones bearing 3-methylpyrazole hinge binding moiety: Highly potent, selective, and time-dependent inhibitors of Cdc7 kinase
Kurasawa, O; Homma, M; Oguro, Y; Miyazaki, T; Mori, K; Uchiyama, N; Iwai, K; Ohashi, A; Hara, H; Yoshida, S; Cho, N
In order to increase the success rate for developing new Cdc7 inhibitors for cancer therapy, we explored a new chemotype which can comply with the previously-constructed pharmacophore model. Substitution of a pyridine ring of a serendipitously-identified Cdc7 inhibitor 2b with a 3-methylpyrazole resulted in a 4-fold increase in potency and acceptable kinase selectivity, leading to the identification of thieno[3,2-d]pyrimidin-4(3H)-one as an alternative scaffold. Structure-activity relationship (SAR) study revealed that incorporation of a substituted aminomethyl group into the 2-position improved kinase selectivity. Indeed, a pyrrolidinylmethyl derivative 10c was a potent Cdc7 inhibitor (IC50 = 0.70 nM) with high selectivity (Cdk2/Cdc7 â¥Â 14,000, ROCK1/Cdc7 = 200). It should be noted that 10c exhibited significant time-dependent Cdc7 inhibition with slow dissociation kinetics, cellular pharmacodynamic (PD) effects, and COLO205 growth inhibition. Additionally, molecular basis of high kinase selectivity of 10c is discussed by using the protein structures of Cdc7 and Cdk2. © 2017 Elsevier Ltd
Cell division cycle 7 (Cdc7); Thieno[3,2-d]pyrimidin-4(3H)-one; Time-dependent Cdc7 inhibition; 2 (cyclopentylmethyl) 6 (3 methyl 1h pyrazol 4 yl)thieno[3,2 d]pyrimidin 4(3h)one; 2 (ethoxymethyl) 6 (3 methyl 1h pyrazol 4 yl)thieno[3,2 d]pyrimidin 4(3h)one; 2 cyclohexyl 6 (3 methyl 1h pyrazol 4 yl)thieno[3,2 d]pyrimidin 4(3h)one; 2 methyl 6 (3 methyl 1h pyrazol 4 yl)thieno[3,2 d]pyrimidin 4(3h)one; 2 methyl 6 (pyridin 4 yl)thieno[3,2 d]pyrimidin 4(3h)one; 2 [(benzylamino)methyl] 6 bromothieno[3,2 d]pyrimidin 4(3h)one; 6 (3 methyl 1h pyrazol 4 yl) 2 (2 pyrrolidin 1 ylethyl)thieno[3,2 d]pyrimidin 4(3h)one; 6 (3 methyl 1h pyrazol 4 yl) 2 morpholin 4 ylthieno[3,2 d]pyrimidin 4(3h)one; 6 (3 methyl 1h pyrazol 4 yl) 2 phenylthieno[3,2 d]pyrimidin 4(3h)one; 6 (3 methyl 1h pyrazol 4 yl) 2 [(methylamino)methyl]thieno[3,2 d]pyrimidin 4(3h)one; 6 (3 pyrazol 4 yl)thieno[3,2 d]pyrimidin 4(3h)one derivative; 6 (pyridin 4 yl) 2 (pyrrolidin 1 ylmethyl)thieno[3,2 d]pyrimidin 4(3h)one; 6 bromo 2 (2 pyrrolidin 1 ylethyl)thieno[3,2 d]pyrimidin 4(3h)one; 6 bromo 2 (chloromethyl)thieno[3,2 d]pyrimidin 4(3h)one; 6 bromo 2 (cyclopentylmethyl)thieno[3,2 d]pyrimidin 4(3h)one; 6 bromo 2 (ethoxymethyl)thieno[3,2 d]pyrimidin 4(3h)one; 6 bromo 2 (piperidin 1 ylmethyl)thieno[3,2 d]pyrimidin 4(3h)one; 6 bromo 2 (pyrrolidin 1 ylmethyl)thieno[3,2 d]pyrimidin 4(3h)one; 6 bromo 2 cyclohexylthieno[3,2 d]pyrimidin 4(3h)one; 6 bromo 2 methylthieno[3,2 d]pyrimidin 4(3h)one; 6 bromo 2 morpholin 4 ylthieno[3,2 d]pyrimidin 4(3h)one; 6 bromo 2 phenylthieno[3,2 d]pyrimidin 4(3h)one; 6 bromo 2 [(3 methylpyrrolidin 1 yl)methyl]thieno[3,2 d]pyrimidin 4(3h)one; 6 bromo 2 [(3 phenylpyrrolidin 1 yl)methyl]thieno[3,2 d]pyrimidin 4(3h)one; cell cycle protein 7; cyclin dependent kinase 2; protein serine threonine kinase; tert butyl(6 bromo 4 oxo 3,4 dihydrothieno[3,2 d]pyrimidin 2 yl)methyl(methyl)carbamate; thieno[3,2 d]pyrimidine derivative; unclassified drug; unindexed drug; 3-methylpyrazole; 6-(3-methyl-1H-pyrazol-4-yl)-2-(pyrrolidin-1-ylmethyl)thieno(3,2-d)pyrimidin-4(3H)-one; CDC7 protein, human; cell cycle protein; protein binding; protein kinase inhibitor; protein serine threonine kinase; pyrazole derivative; pyrimidinone derivative; recombinant protein; Rho kinase; ROCK1 protein, human; thiophene derivative; Article; binding site; cancer inhibition; controlled study; drug design; drug identification; drug potency; drug selectivity; drug structure; drug synthesis; enzyme inhibition; enzyme structure; IC50; in vitro study; molecular docking; nonhuman; pharmacodynamics; pharmacophore; structure activity relation; antagonists and inhibitors; biosynthesis; chemistry; genetics; human; kinetics; metabolism; protein tertiary structure; synthesis; Binding Sites; Cell Cycle Proteins; Cyclin-Dependent Kinase 2; Humans; Inhibitory Concentration 50; Kinetics; Molecular Docking Simulation; Protein Binding; Protein Kinase Inhibitors; Protein Structure, Tertiary; Protein-Serine-Threonine Kinases; Pyrazoles; Pyrimidinones; Recombinant Proteins; rho-Associated Kinases; Structure-Activity Relationship; Thiophenes