Cyclin Dependent Kinase 9 Inhibitors for Cancer Therapy

Abstract

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.

Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC)

“…CDK1–4, CDK6 and CDK11 regulate cell cycle, while CDK7–9 are involved in transcription regulation. 1–4 Over the past two decades, a number of CDK inhibitors have entered clinical trials for the treatment of cancer. 5–11 Off-target dose limiting toxicities are a significant problem with the development of CDK inhibitors.…”

Synthesis of aminopyrazole analogs and their evaluation as CDK inhibitors for cancer therapy

“…Members of cyclin-dependent kinase (CDK) family of proteins are involved in the regulation of cell cycle and transcription. 1, 2 Thus pharmaceutical companies and academic laboratories have targeted CDK for cancer therapy. A number of CDK inhibitors built on different core structures (Figure 1) have been developed and a handful of CDK inhibitors have advanced through clinical trials and obtained approval or orphan drug status from the FDA (Flavopiridol - pan CDK, CLL; Palbociclib - CDK4/6, breast cancer; Ribociclib - CDK4/6, breast cancer; and Abemaciclib - CDK4/6, breast cancer).…”

Active K‐RAS induces the coherent rotation of epithelial cells: A model for collective cell invasion in vitro

“…Cyclins are regulatory subunits that bind to the CDK, resulting in activation of the kinase. Most members of the CDK family form a CDK/cyclin (CCN) complex and are involved in regulation of the cell cycle . Against our expectation, downregulation of various CDKs had no effect on the cross‐product and velocity of cell clusters (Figure B); this might be due to the incomplete knockdown of CDKs in the cells (Figure A).…”

“…In contrast, among various cyclins, the knockdown of CCNB1 reduced both cross‐product and velocity. Cyclin B1 is expressed in the late G 2 to M phase of the cell cycle and regulates CDK1 activity and cell proliferation . As shown in Figure C, CCNB1 knockdown suppressed cell proliferation, but CDK1 knockdown did not.…”