Vol. 6, Issue 11 (2017)

Author(s):
Priyanka Devlal and Anita Singh

Abstract:
The cell-cycle is tremendously complex process and strictly controlled by cellular proteins called ‘Cyclin-dependent kinases’ (CDKs). Because of their critical contribution in cell division and their dysregulation in many cancers, CDKs have become an intense area of research for >20 years and several CDK-inhibitors (CDKIs) were developed. Initial results with broadly acting, first generation, pan-CDK inhibitors including flavopiridol, olomoucine, UCN-01 were almost disappointing due to limited efficacy and high toxicities observed in-vivo. To overcome these failures, Second-generation CDK inhibi¬tors with high selectivity and specificity were enormously researched and developed. Based on impressive results in clinical investigations, FDA granted approval to three highly-specific CDK’4/6 inhibitors including; palbociclib (PD0332991), abemaciclib (LY2835219) and ribociclib (LEE011) for treatment of` patients with ‘HR-positive’, ‘HER2-negative’ advanced or metastatic` breast cancer. In this Review’, we’ll focus on CDKs, their contribution in cell-cycle and cancer, development and failure of pan-CDK inhibitors and currently approved CDK4/6 inhibitors with their preclinical’ and clinical study data that manifested their benefit in breast cancer’ treatment. In future, translational studies for coordinated assessment of the important biomarkers of clinical sensitivity and complete understanding of intersection of pharmacology’ and biology of CDKIs is required for more clinical success in the cancer treatment.