2-amino-6-methyl-4-(3-pyridinyl)-5-6-7-8-tetrahydroquinoline-3-carbonitrile and Neoplasms

Inhibition of cyclin-dependent kinases (CDKs) has become an effective therapeutic strategy for treating various diseases, especially cancer. Over almost three decades, although great efforts have been made to discover CDK inhibitors, many of which have entered clinical trials, only four CDK inhibitors have been approved. In the process of CDK inhibitor development, many difficulties and misunderstandings have hampered their discovery and clinical applications, which mainly include inadequate understanding of the biological functions of CDKs, less attention paid to pan- and multi-CDK inhibitors, nonideal isoform selectivity of developed selective CDK inhibitors, overlooking the metabolic stability of early discovered CDK inhibitors, no effective resistance solutions, and a lack of available combination therapy and effective biomarkers for CDK therapies. After reviewing the mechanisms of CDKs and the research progress of CDK inhibitors, this perspective summarizes and discusses these difficulties or lessons, hoping to facilitate the successful discovery of more useful CDK inhibitors.

Topics: Antineoplastic Agents; Cell Cycle; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinases; Drug Discovery; Humans; Neoplasms; Protein Kinase Inhibitors

Cyclin-dependent kinases 8 (CDK8) regulates transcriptional process via associating with the mediator complex or phosphorylating transcription factors (TF). Overexpression of CDK8 has been observed in various cancers. It mediates aberrant activation of Wnt/β-catenin signaling pathway, which is initially recognized and best studied in colorectal cancer (CRC). CDK8 acts as an oncogene and represents a potential target for developing novel CDK8 inhibitors in cancer therapeutics. However, other study has revealed its contrary role. The function of CDK8 is context dependent. Even so, a variety of potent and selective CDK8 inhibitors have been discovered after crystal structures were resolved in two states (active or inactive). In this review, we summarize co-crystal structures, biological mechanisms, dysregulation in cancers and recent progress in the field of CDK8 inhibitors, trying to offer an outlook of CDK8 inhibitors in cancer therapy in future.

Topics: Colorectal Neoplasms; Cyclin-Dependent Kinase 8; Drug Discovery; Humans; Mediator Complex; Molecular Structure; Neoplasms; Oncogenes; Protein Kinase Inhibitors; Wnt Signaling Pathway

Cyclin-dependent kinase 8 (CDK8) plays a vital role in regulating transcription either through its association with the Mediator complex or by phosphorylating transcription factors. Myriads of genetic and biochemical studies have established CDK8 as a key oncogenic driver in many cancers. Specifically, CDK8-mediated activation of oncogenic Wnt-β-catenin signaling, transcription of estrogen-inducible genes, and suppression of super enhancer-associated genes contributes to oncogenesis in colorectal, breast, and hematological malignancies, respectively. However, while most research supports the role of CDK8 as an oncogene, other work has raised the possibility of its contrary function. The diverse biological functions of CDK8 and its seemingly context-specific roles in different types of cancers have spurred a great amount of interest and perhaps an even greater amount of controversy in the development of CDK8 inhibitors as potential cancer therapeutic agents. Herein, we review the latest landscape of CDK8 biology and its involvement in carcinogenesis. We dissect current efforts in discovering CDK8 inhibitors and attempt to provide an outlook at the future of CDK8-targeted cancer therapies.

Topics: Antineoplastic Agents; Cyclin-Dependent Kinase 8; Cytokines; Humans; Male; Molecular Targeted Therapy; Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Transcription Factors; Tumor Escape