A Novel Approach for the Development of Selective Cdk4 Inhibitors: Library Design Based on Locations of Cdk4 Specific Amino Acid Residues

• DOI: 10.1021/jm010326y
• Publication Date: 2002-07-26T04:45:26Z
• Authors: Teruki Honma; Takashi Yoshizumi; Noriaki Hashimoto; Kyoko Hayashi; Nobuhiko Kawanishi; Kazuhiro Fukasawa; Tohru Takaki; Chinatsu Ikeura; Mari Ikuta; Ikuko Suzuki-Taka...; Takashi Hayama; Susumu Nishimura; Hajime Morishima
• Keywords: Lead compound; Structure–activity relationship; Pyrazole

Identification of a selective inhibitor for particular protein kinase without inhibition other kinases is critical use as biological tool or drug. However, this very difficult because there are hundreds homologous and their domains including the ATP binding pocket have common folding pattern. To address issue, we applied following structure-based approach designing Cdk4 inhibitors: (1) identification specifically altered amino acid residues around in by comparison 390 representative kinases, (2) prediction appropriate positions to introduce substituents lead compounds based on locations modes compounds, (3) library design interact with supported de novo programs. Accordingly, Asp99, Thr102, Gln98 Cdk4, which located p16 region, were selected first target specific interactions Cdk4. Subsequently, 5-position pyrazole ring pyrazol-3-ylurea class compound (2a) was predicted be suitable position substituents. We then designed chemical substituted alkylaminomethyl groups output structures Thus identified highly potent inhibitor, 15b, 5-chloroindan-2-ylaminomethyl group. Compound 15b showed higher selectivity over those not only Cdk1/2 (780-fold/190-fold) but also many (>430-fold) that been tested thus far. The structural basis analyzed combining molecular modeling X-ray analysis mimic Cdk2-inhibitor complex. results suggest hydrogen bond carboxyl group Asp99 hydrophobic van der Waals contact side chains Thr102 important. found cause cell cycle arrest Rb(+) cancer line G(1) phase, indicating it good tool.