Cyclin Dependent Kinase (CDK) Inhibitors as Anticancer Drugs: Recent Advances (2015–2019)
Abstract
Sustained proliferative capacity and gene dysregulation are hallmarks of cancer. In mammalian cells, cyclin-dependent kinases (CDKs) regulate key checkpoints of the cell cycle and crucial transcriptional events in response to extracellular and intracellular stimuli. Significant clinical benefits have been demonstrated by dual CDK4/6 inhibitors such as palbociclib, ribociclib, and abemaciclib, which are approved for hormone receptor-positive metastatic breast cancer. Early-stage results with the CDK7 inhibitor SY-1365 in solid tumors have revitalized interest in the CDK research field. This review summarizes major advances in CDK inhibitor research between 2015 and 2019, with emphasis on transcriptional CDK inhibitors, new strategies such as targeted degradation, and molecules in clinical development.
Introduction
The hallmarks of cancer, originally outlined by Hanahan and Weinberg and later expanded by Fouad, offer a framework for therapeutic intervention. Uncontrolled replication and transcriptional dysregulation are common features of many cancers and have been focal points of cancer drug development.
Cyclin-dependent kinases are serine/threonine kinases first discovered for their role in cell cycle control. CDKs depend on cyclins for their stability, activation, and downstream phosphorylation activities. The cell also contains endogenous CDK inhibitors (CKIs) that modulate these complexes. These components interact to ensure orderly progression through the cell cycle. Beyond this role, CDKs and their associated proteins contribute to transcriptional regulation, DNA damage repair, metabolism, angiogenesis, epigenetics, and more.
The human genome contains 20 CDKs and 29 cyclins. CDKs can be grouped by their primary functions: CDK1, 4, and 5 are mainly involved in cell cycle regulation, while CDK7, 8, 9, 11, and 20 are classified as transcriptional CDKs. Although these classifications exist, some CDKs, such as CDK7, participate in both cell cycle and transcriptional activities.
CDKs in the Cell Cycle
The mammalian cell cycle includes four phases: G1, S (DNA synthesis), G2, and M (mitosis). Specific CDKs and cyclins regulate each transition. In early G1, cyclin D partners with CDK4/6 to phosphorylate the Rb protein, releasing E2F transcription factors and initiating transcription of genes required for progression. In late G1, CDK2/cyclin E completes Rb phosphorylation, and cells enter S phase. CDK2/cyclin A continues to regulate S phase, while CDK1/cyclin B controls mitosis. Despite this elaborate regulation, CDK1 alone is essential for the mammalian cell cycle due to compensatory mechanisms observed in knockout models.
CDKs in Transcription
Transcription in mammalian cells is a multi-step, tightly regulated process. CDKs play central roles by phosphorylating the carboxy-terminal domain (CTD) of RNA polymerase II (RNAPII). Phosphorylation of Ser5 initiates transcription; Ser2 phosphorylation facilitates elongation. CDK7, CDK8/19, CDK9, CDK12, CDK13, CDK10, and CDK11 are involved in different transcriptional phases. For example, CDK7 acts as a CDK-activating kinase (CAK) and regulates both transcription and the cell cycle. CDK12 and CDK13 support transcription elongation and RNA processing, including alternative splicing. CDK10 and CDK11 are involved in transcription regulation and splicing, as well as other cellular processes.
Other CDKs
CDKs such as CDK5, 14–18, and 20 perform specialized functions. CDK5, expressed primarily in neurons, regulates neurodevelopmental proteins and has roles in cancer progression and treatment resistance. CDK14 and others influence signaling pathways like Wnt/β-catenin. CDK20 may interact with signaling pathways and immune responses in cancer.
CDKs in Cancer
Aberrant expression of CDKs, cyclins, and CKIs is common in cancer. The cyclin D-CDK4/6-p16-Rb pathway is frequently altered, promoting uncontrolled proliferation. CDK4/6 inhibitors show clinical efficacy in breast cancer and are under investigation for other tumors. Resistance mechanisms include Rb loss, CDK amplification, and cyclin gene mutations. Combination strategies, particularly with PI3K or RAS pathway inhibitors, are under study to overcome resistance.
Cancer stem cells and immune evasion are also influenced by CDK activity. CDK inhibitors have shown potential in targeting cancer stem cells and enhancing immunotherapy responses, such as through downregulation of PD-L1.
Structural Insights
CDK structures, such as CDK2/cyclin A, have provided insight into kinase regulation. Structural differences among CDKs contribute to selectivity and inform drug design. Techniques like hydrogen-deuterium exchange and cryo-EM may further reveal CDK regulation and interaction.
CDK Inhibitors
Recent years have seen progress in developing ATP-competitive, covalent, allosteric, and degrader-based CDK inhibitors. Early pan-CDK inhibitors had limited clinical success due to toxicity. New generations are more selective. Covalent inhibitors like SY-1365 (CDK7) and THZ531 (CDK12/13) have demonstrated promising preclinical activity.
Targeted protein degradation via PROTACs and hydrophobic tagging (HyT) is an emerging strategy. Selective degraders for CDK4/6, CDK8, and CDK9 have been developed. These offer prolonged target inhibition and may bypass resistance seen with classical inhibitors.
Reversible CDK inhibitors continue to be optimized for selectivity and efficacy. Several are in clinical development for solid and hematologic malignancies. Notable compounds include ICEC0942 (CDK7), TP-1287 (CDK9), and FN-1501 (CDK2/FLT3). Many CDK4/6 inhibitors are being evaluated for brain penetration and resistance profiles.
Conclusion and Outlook
The CDK inhibitor field has evolved substantially. Selective CDK4/6 inhibitors have changed clinical practice in breast cancer and show promise in other malignancies. Future directions include novel chemotypes, covalent inhibition, targeted degradation, and allosteric modulation. Technological advances will further illuminate PF-06873600 CDK biology and support development of highly selective, effective anticancer agents.