Discovery of N-(4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)-4-(4-methylpiperazin-1-yl)quinazolin-7-amine as a Novel, Potent, and Oral Cyclin-Dependent Kinase Inhibitor against Haematological Malignancies.

Abstract

Hematologic malignancies (HM) start in blood forming tissue or in the cells of the immune system. Cyclin-dependent kinases (CDKs) regulate cell cycle progression, and some of them control cellular transcription. CDK inhibition can trigger apoptosis and could be particularly useful in hematological malignancies. Herein, we describe our efforts toward the discovery of a novel series of quinazoline derivatives as CDK inhibitors. Intensive structural modifications lead to the identification of compound 37d as the most active inhibitors of CDKs 1, 2, 4, 8 and 9 with balancing potency and selectivity against CDKs. Further biological studies revealed that compound 37d can arrest the cell cycle and induce apoptosis via activating PARP and caspase 3. More importantly, compound 37d showed good antitumor efficacy in multiple HM mice xenograft models with no obvious toxicity. These results indicated that CDK 1, 2, 4, 8, and 9 inhibitors could be potentially used to treat certain hematologic malignancies.

• Authors: Jianhang Huang, Xinren Wang, Ruinan Dong, Xiaoyue Liu, Hongmei Li, Tianyi Zhang, Junyu Xu, Chenhe Liu, Yanmin Zhang, Shaohua Hou, Weifang Tang, Tao Lu, Yadong Chen
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 17 Pg. 12548-12571 (09 09 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 34415148 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• CDK9 protein, human
• Cyclin-Dependent Kinase 9

Topics

• Administration, Oral
• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Area Under Curve
• Catalytic Domain
• Cell Line, Tumor
• Cyclin-Dependent Kinase 9 (chemistry, metabolism)
• Half-Life
• Humans
• Mice
• Molecular Structure
• Protein Binding
• Protein Kinase Inhibitors (chemistry, pharmacokinetics, pharmacology)
• Structure-Activity Relationship
• Xenograft Model Antitumor Assays