Development of Highly Potent and Selective Pyrazolopyridine Inhibitor of CDK8/19

CDK8 and its paralog CDK19 are cyclin-dependent kinases that are core components of the so-called Mediator complex that has essential roles as a positive and negative regulator of gene expression. Several efforts to develop inhibitors have yielded natural and synthetic ATP-competitive compounds including cortistatin A, Sel120, BCD-115, CCT251921 (1), and MSC2530818 (2). Here, we used a hybridization approach starting from CCT251921 and MSC2530818 to derive new inhibitors with the aim of developing highly potent and selective inhibitors of CDK8/19. Initial compounds suffered from rapid aldehyde oxidase-mediated metabolism. This liability was overcome by utilizing a pyrazolopyridine hinge binder with a chlorine at the C-3 position. These efforts resulted in JH-XVI-178 (compound 15), a highly potent and selective inhibitor of CDK8/19 that displays low clearance and moderate oral pharmacokinetic properties.

 

Comments:

CDK8 and its paralog CDK19 are cyclin-dependent kinases that play important roles in regulating gene expression as core components of the Mediator complex. The Mediator complex functions both as a positive and negative regulator of gene expression, influencing various cellular processes.

In the quest to develop inhibitors targeting CDK8/19, several natural and synthetic ATP-competitive compounds have been investigated, including cortistatin A, Sel120, BCD-115, CCT251921 (1), and MSC2530818 (2). Among these compounds, CCT251921 and MSC2530818 were used as starting points for a hybridization approach in order to generate new inhibitors with enhanced potency and selectivity against CDK8/19.

One challenge encountered in the development of these inhibitors was the rapid metabolism mediated by aldehyde oxidase, which limited their effectiveness. However, this issue was addressed by incorporating a pyrazolopyridine hinge binder with a chlorine atom at the C-3 position. This modification helped to overcome the metabolic liability associated with the initial compounds.

As a result of these efforts, JH-XVI-178 (also referred to as compound 15) was developed. JH-XVI-178 is a highly potent and selective inhibitor of CDK8/19, demonstrating both low clearance and moderate oral pharmacokinetic properties. These characteristics make it a promising candidate for further development as a potential therapeutic agent targeting CDK8/19 in the regulation of gene expression.

Related Products

Cat.No.	Product Name	Information
S8387	MSC2530818	MSC2530818, a CDK8 inhibitor with the IC50 of 2.6 nM, displays excellent kinase selectivity, biochemical and cellular potency, microsomal stability, and is orally bioavailable.

Related Targets

CDK