Cyclin-dependent kinase (CDK) (pan-CDK)

Cyclin-dependent kinases (CDKs) are a large family of serine/threonine protein kinases that act as the primary regulators of the eukaryotic cell cycle and gene transcription (Malumbres, 2014, Nature Reviews Cancer). The pan-CDK designation refers to therapeutic agents designed to inhibit a broad spectrum of these kinases, typically including CDK1, CDK2, CDK4, CDK6, and CDK9. In many malignancies, the regulatory mechanisms governing CDKs are disrupted, resulting in uncontrolled cell proliferation and resistance to apoptosis. Pan-CDK inhibitors aim to counteract this by inducing multi-phase cell cycle arrest and suppressing the transcription of essential pro-survival genes. Despite showing significant anti-tumor activity in preclinical models, the clinical development of pan-CDK inhibitors has been hampered by substantial systemic toxicities, such as myelosuppression and gastrointestinal distress, which arise from the inhibition of CDKs in normal, healthy tissues (Asghar et al., 2015, Nature Reviews Drug Discovery). As a result, while pan-CDK inhibition remains a potent strategy, much of the pharmaceutical focus has transitioned toward more isoform-selective inhibitors to improve the safety profile.

Other names

CDK familyCyclin-dependent kinasesCell cycle-dependent kinases

Pan-CDK inhibitors function as ATP-competitive inhibitors that target the catalytic subunits of multiple cyclin-dependent kinases (CDKs), including those involved in cell cycle control (CDK1, 2, 4, 6) and transcriptional regulation (CDK7, 9). By blocking these kinases, the drugs prevent the phosphorylation of the Retinoblastoma (Rb) protein and inhibit RNA polymerase II activity, leading to cell cycle arrest and the downregulation of short-lived survival proteins like MCL-1 (Asghar et al., 2015, Nature Reviews Drug Discovery).