Novel Medicinal Chemistry Strategies Targeting CDK5 for Drug Discovery

作者：Tang, Wentao; Lin, Congcong; Yu, Quanwei; Zhang, Dan; Liu, Yun; Zhang, Lele; Zhou, Zhilan; Zhang, Jifa^*; Ouyang, Liang^*

来源：Journal of Medicinal Chemistry, 2023, 66(11): 7140-7161.

DOI：10.1021/acs.jmedchem.3c00566

• CYCLIN-DEPENDENT KINASE-5
• BRAIN-SPECIFIC ACTIVATOR
• MANTLE-CELL LYMPHOMA
• PHASE-I TRIAL
• NEURITE OUTGROWTH
• PHOSPHOCHOLINE CYTIDYLYLTRANSFERASE-BETA-2
• SELECTIVE INHIBITORS
• POTENTIAL TREATMENT
• GENE-EXPRESSION
• DNA-DAMAGE

Cyclin-dependentkinase 5 (CDK5) protein plays an important rolenot only in the central nervous system but also in the periphery,including immune response, regulation of insulin secretion, and cancerdevelopment and progression. Consequently, targeting the CDK5 proteinis a potential strategy for the treatment of many diseases, especiallycancer and neurodegenerative diseases. To date, numerous pan-CDK inhibitorshave entered clinical trials. Nevertheless, limited clinical efficacyand severe adverse effects have prompted the application of new techniquesto optimize clinical efficacy and minimize adverse events. In thisPerspective, we highlight the protein properties, biofunctions, relevantsignaling pathways, and associations with cancer development and proliferationof CDK5, and analyze the clinical status of pan-CDK inhibitors andthe preclinical status of CDK5-specific inhibitors. In addition, CDK5-selectiveinhibitors, protein-protein interaction inhibitors, proteolytic-targetingchimera (PROTAC) degraders, and dual-target CDK5 inhibitors are discussed.

• 单位
  哈尔滨医科大学; 四川大学