Structure-Based Design, Synthesis, and Biological Evaluation of Potent and Selective Macrocyclic Checkpoint Kinase 1 Inhibitors

• Published in: Journal of medicinal chemistry Vol. 50; no. 7; pp. 1514 - 1527
• Main Authors: Tao, Zhi-Fu, Wang, Le, Stewart, Kent D, Chen, Zehan, Gu, Wendy, Bui, Mai-Ha, Merta, Philip, Zhang, Haiying, Kovar, Peter, Johnson, Eric, Park, Chang, Judge, Russell, Rosenberg, Saul, Sowin, Thomas, Lin, Nan-Horng
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 05.04.2007; Amer Chemical Soc
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Camptothecin - pharmacology; Cell Line, Tumor; Checkpoint Kinase 1; Chemistry, Medicinal; Crystallography, X-Ray; DNA Damage; Doxorubicin - pharmacology; Drug Design; Drug Screening Assays, Antitumor; Drug Synergism; General aspects; Humans; Life Sciences & Biomedicine; Macrocyclic Compounds - chemical synthesis; Macrocyclic Compounds - chemistry; Macrocyclic Compounds - pharmacology; Medical sciences; Miscellaneous; Models, Molecular; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinases - chemistry; Protein Kinases - metabolism; Science & Technology; Structure-Activity Relationship; Urea - analogs & derivatives; Urea - chemical synthesis; Urea - chemistry; Urea - pharmacology; CANCER-CELLS; NS3 SERINE-PROTEASE; DNA-DAMAGE CHECKPOINT; CAMPTOTHECIN; 7-HYDROXYSTAUROSPORINE UCN-01; ABROGATION; CHK1 INHIBITORS; CYTOTOXICITY; S-PHASE CHECKPOINT; P53; Antineoplastic agent; Potentiation; Cytotoxicity; Selectivity; Uterine cervix; Doxorubicin; Synergism; Macrocycle; Signal transduction; Alkaloid; Structure activity relation; Ureas; Cyclophane; Colon; Chemical synthesis; Tumor cell; Oxygen nitrogen heterocycle; Human; Drug combination; Enzyme; Transferases; Enzyme inhibitor; Tricyclic compound; Organic chlorine compounds; In vitro; Hela cell line; Cell line; Protein kinase; Anthracyclins
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm061247v

Based on the crystallographic analysis of a urea−checkpoint kinase 1 (Chk1) complex and molecular modeling, a class of macrocyclic Chk1 inhibitors were designed and their biological activities were evaluated. An efficient synthetic methodology for macrocyclic ureas was developed with Grubbs metathesis macrocyclization as the key step. The structure−activity relationship studies demonstrated that the macrocyclization retains full Chk1 inhibition activity and that the 4-position of the phenyl ring can tolerate a wide variety of substituents. These novel Chk1 inhibitors exhibit excellent selectivity over a panel of more than 70 kinases. Compounds 5b, 5c, 5f, 15, 16d, 17g, 17h, 17k, 18d, and 22 were identified as ideal Chk1 inhibitors, which showed little or no single-agent activity but significantly potentiate the cytotoxicities of the DNA-damaging antitumor agents doxorubicin and camptothecin. These novel Chk1 inhibitors abrogate the doxorubicin-induced G2 and camptothecin-induced S checkpoint arrests, confirming that their potent biological activities are mechanism-based through Chk1 inhibition.