14-methyl-20-oxa-5-7-14-26-tetraazatetracyclo(19.3.1.1(2-6).1(8-12))heptacosa-1(25)-2(26)-3-5-8(27)-9-11-16-21-23-decaene and Neoplasms

Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, is an attractive therapeutic target for many cancers, especially for cancers driven by transcriptional dysregulation. In particular, CDK9 promotes RNA polymerase II pause/release, a rate-limiting step in normal transcriptional regulation that is frequently dysregulated in cancers. Emerging evidence indicates that selective CDK9 inhibition or degradation may provide a therapeutic benefit against certain cancers. Indeed, the development of CDK9 modulators (inhibitors and degraders) has attracted great attention, with several molecules currently under clinical development. This review provides an overview of recent advances in CDK9 modulators in general, with special emphasis on compounds under clinical evaluation and new emerging strategies, such as proteolysis targeting chimeras (PROTACs).

Topics: Animals; Antineoplastic Agents; Chemistry, Pharmaceutical; Cyclin-Dependent Kinase 9; Drug Development; Humans; Molecular Docking Simulation; Neoplasms; Protein Kinase Inhibitors; Protein Structure, Secondary

Cyclin-dependent kinase 2 (CDK2) drives the progression of cells into the S- and M-phases of the cell cycle. CDK2 activity is largely dispensable for normal development, but it is critically associated with tumor growth in multiple cancer types. Although the role of CDK2 in tumorigenesis has been controversial, emerging evidence proposes that selective CDK2 inhibition may provide a therapeutic benefit against certain tumors, and it continues to appeal as a strategy to exploit in anticancer drug development. Several small-molecule CDK2 inhibitors have progressed to the clinical trials. However, a CDK2-selective inhibitor is yet to be discovered. Here, we discuss the latest understandings of the role of CDK2 in normal and cancer cells, review the core pharmacophores used to target CDK2, and outline strategies for the rational design of CDK2 inhibitors. We attempt to provide an outlook on how CDK2-selective inhibitors may open new avenues for cancer therapy.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Cyclin-Dependent Kinase 2; Drug Design; Humans; Neoplasms; Protein Binding; Protein Conformation; Protein Kinase Inhibitors

Cyclin dependent kinase (CDK) inhibitors have been the topic of intense research for nearly 2 decades due to their widely varied and critical functions within the cell. Recently CDK9 has emerged as a druggable target for the development of cancer therapeutics. CDK9 plays a crucial role in transcription regulation; specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells. Focused chemical libraries based on a plethora of scaffolds have resulted in mixed success with regard to the development of selective CDK9 inhibitors. Here we review the regulation of CDK9, its cellular functions, and common core structures used to target CDK9, along with their selectivity profile and efficacy in vitro and in vivo.

Topics: Animals; Cyclin-Dependent Kinase 9; Drug Discovery; Flavonoids; Humans; Macrocyclic Compounds; Models, Molecular; Neoplasms; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Triazines