The history and future of targeting cyclin-dependent kinases in cancer therapy

By U. Asghar, A. Witkiewicz, N. Turner, E. Knudsen. Nature reviews. Drug discovery, 2015

1,602 citations recorded by the source corpus.

Cancer represents a pathological manifestation of uncontrolled cell division; therefore, it has long been anticipated that our understanding of the basic principles of cell cycle control would result in effective cancer therapies. In particular, cyclin-dependent kinases (CDKs) that promote transition through the cell cycle were expected to be key therapeutic targets because many tumorigenic events ultimately drive proliferation by impinging on CDK4 or CDK6 complexes in the G1 phase of the cell cycle. Moreover, perturbations in chromosomal stability and aspects of S phase and G2/M control mediated by CDK2 and CDK1 are pivotal tumorigenic events. Translating this knowledge into successful clinical development of CDK inhibitors has historically been challenging, and numerous CDK inhibitors have demonstrated disappointing results in clinical trials. Here, we review the biology of CDKs, the rationale for therapeutically targeting discrete kinase complexes and historical clinical results of CDK inhibitors. We also discuss how CDK inhibitors with high selectivity (particularly for both CDK4 and CDK6), in combination with patient stratification, have resulted in more substantial clinical activity.

Subfields: Cell Biology, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/5f0b6c13b9d8ba6d49c8ca8725a9d26273bad017

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Citations in the corpus

• A perspective on multi-target drug discovery and design for complex diseases (2018, background): “Among them, palbociclib, abemaciclib and ribociclib were approved by FDA as breast cancer therapy in this time frame [26].”
• Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor–Positive Breast Cancer (2016, neutral): “CDK4/6 inhibitors have shown activity in breast cancer, particularly in combination with endocrine therapy (13, 23, 29).”
• TARGETING CDK4 AND CDK6: FROM DISCOVERY TO THERAPY (2015, neutral): “4–5 nmol/L CDK 9: 57 nmol/L CDK1: >1 μmol/L CDK2: >500 nmol/L (1, 88) PK Tmax 4.”