Structure-Based Design of CSDK4-Specific Inhibitors

摘要

Distinct cancer types have been correlated with several proteins that are involved in the G1 to S transition of the mammalian cell cycle (Funk, 1999; Molinari, 2000). In particular, the inability to inhibit the activity of the paralogs cyclin-dependent kinases 4 and 6 (CDK4/6) are implicated in more than 80% of human neoplasias (Ortega et al., 2002). For example, the gene encoding the CDK4/6 inhibitory protein, p16INK4, is deleted or mutated in the majority of leukemias, bladder cancers and familial melanomas (Roussel, 1999). The CDK4/6 stimulatory subunit, cyclin Dl, is commonly found to be overexpressed or gene amplified in spontaneous breast cancers (Donnellan and Chetty, 1998; Khoo et al. , 2002), and overexpression of cyclin Dl in mice leads to death due to breast cancer (Wang et al., 1994). Finally, CDK4 itself is overexpressed or gene amplified in about one third of breast cancers (Ortega et al., 2002). Together, these observations indicate that deregulation of the G1 to S transition of the mammalian cell cycle is tightly linked to the onset of several different cancer types, and that the CDK4/6 protein, in particular, is an excellent candidate for targeted inhibition for the treatment of breast cancer.