Identification of Potent 5‐Pyrimidinyl‐2‐aminothiazole CDK4, 6 Inhibitors with Significant Selectivity over CDK1, 2, 5, 7, and 9.

Abstract

over CDK1, 2, 5, 7, and 9. -Screening and medicinal chemistry techniques, supported by molecular modeling, identifies compound (I) containing the novel pyrimidinylaminothiazole scaffold as a potent CDK4 inhibitor. Introduction of a methyl group at the C-5 or C-6 position on the pyrimidine ring directed toward the gate keeper residue of CDK4 (Phe93), greatly enhances the CDK4 selectivity over other CDK family kinases. (I) shows sufficient aqueous solubility and potently inhibits pRb phosphorylation and BrdU incorporation in tumor models. -(SHIMAMURA, T.; SHIBATA, J.; KURIHARA, H.; MITA, T.; OTSUKI, S.; SAGARA, T.; HIRAI, H.; IWASAWA*, Y.; Bioorg.

Successful Treatment of Animal Models of Rheumatoid Arthritis with Small-Molecule Cyclin-Dependent Kinase Inhibitors

“…5A). It selectively inhibited CDK4 and CDK6, both of which have been shown to have indistinguishable activities in vitro (20). The IC 50 for CDK4 and CDK6 was 9.2 and 7.8 nM, respectively, which were at least 100-fold less than concentrations for other CDKs.…”

“…A stock solution of alvocidib prepared in DMSO was diluted to working concentrations before each experiment. In addition, a CDK4/6-selective inhibitor compound A (N-{5-[2-(cyclohexyloxy)-6-methylpyrimidin-4-yl]-1,3-thiazol-2-yl}-5-[(4-methylpiperazin-1-yl)methyl]pyrazin-2-amine), which was characterized as compound 4 in the previous report (20), was synthesized at Merck-Banyu. It was dissolved in DMSO for in vitro analyses and in 5% glucose containing 10 mM citrate buffer (pH 4) for treatment of mice.…”

“…This agent has broad activity, inhibiting all CDKs and some other kinases (29). To study further whether cell cycle inhibition by CDK4/6 inhibition had a important role in ameliorating arthritis, a selective inhibitor, compound A, was synthesized (20). It is an aminothiazole CDKI that is structurally unrelated to alvocidib (Fig.…”

Targeting CDK6 in cancer: State of the art and new insights

“…92,107,108 In addition to the above clinical experimental drug compounds, a few pre-clinical CDK4/6 inhibitors, i.e., 7X, AMG925, Compound 6, Compound A and PD0183812, have been reported. [109][110][111][112][113] The chemical structures and CDK inhibitory activity of these compounds are summarized in Table 3. A close examination of the chemical structures of PD0332991, LEE011, LY2835219, AMG925 and Compound A reveals a general N-NH-N sequence of the pyrimidine-amine-pyridine or pyrazineamine-thiazole system.…”

Biological characterization of 2-aminothiazole-derived Cdk4/6 selective inhibitor in vitro and in vivo

“…We have developed a Cdk4, six selective inhibitor compound named Compound A which is based on a novel 5-pyrimidinyl-2-aminothiazole structure. 16 This compound was identified by screening the compound sample repository and modifying the initial leads, supported by molecular modeling. In the present report, we describe the biological characterization of Compound A in vitro and in vivo.…”