Analyzing the scaffold diversity of cyclin‐dependent kinase inhibitors and revisiting the clinical and preclinical pipeline

Abstract

Kinases have gained an important place in the list of vital therapeutic targets because of their overwhelming clinical success in the last two decades. Among various clinically validated kinases, the cyclin‐dependent kinases (CDK) are one of the extensively studied drug targets for clinical development. Food and Drug Administration has approved three CDK inhibitors for therapeutic use, and at least 27 inhibitors are under active clinical development. In the last decade, research and development in this area took a rapid pace, and thus the analysis of scaffold diversity is essential for future drug design. Available reviews lack the systematic study and discussion on the scaffold diversity of CDK inhibitors. Herein we have reviewed and critically analyzed the chemical diversity present in the preclinical and clinical pipeline of CDK inhibitors. Our analysis has shown that although several scaffolds represent CDK inhibitors, only the amino‐pyrimidine is a well‐represented scaffold. The three‐nitrogen framework of amino‐pyrimidine is a fundamental hinge‐binding unit. Further, we have discussed the selectivity aspects among CDKs, the clinical trial dose‐limiting toxicities, and highlighted the most advanced clinical candidates. We also discuss the changing paradigm towards selective inhibitors and an overview of ATP‐binding pockets of all druggable CDKs. We carefully analyzed the clinical pipeline to unravel the candidates that are currently under active clinical development. In addition to the plenty of dual CDK4/6 inhibitors, there are many selective CDK7, CDK9, and CDK8/19 inhibitors in the clinical pipeline.

Lessons Learned from Past Cyclin-Dependent Kinase Drug Discovery Efforts

“…We investigated the chemical scaffolds of pan-CDK inhibitors in clinical trials and found that the most commonly used scaffolds include 5-hydroxy-4 H -chromen-4-one, 9 H -purin-6-amine, thiazol-2-amine, pyrimidin-2-amine, 1 H -pyrazole, pyrazolo­[1,5- a ]­pyrimidin-7-amine, and 1 H -pyrazol-4-amine, as depicted in Figure . These scaffolds are very important for binding CDKs because they provide atoms that can form critical hydrogen bonds with the hinge regions of CDKs …”

“…In 2021, the oral selective CDK7 inhibitor XL102 (structure undisclosed), developed by Exelixis, entered a phase I trial for multiple solid tumors, and patients are being recruited (NCT04726332). BCD-115 (24), a selective oral CDK8 inhibitor, entered a phase II trial for breast cancer treatment in 2017 (NCT03065010).…”

“…as examples, which talk about CDK2, CDK7, CDK8, and CDK9 (twice)). − So far, specific insights on CDK2, CDK4/6, CDK7, CDK8, CDK9, or CDK12 have been reviewed in different articles. A few articles center upon all members of the CDK family, but they usually concentrate on only one aspect of CDK drug discovery. − Several reviews specifically provide information on clinical trials of CDK inhibitors, scaffolds of CDK inhibitors, CDK regulators, and types of CDK inhibitors . Unlike these articles, this perspective comprehensively summarizes the biology of all members of the CDK family and CDK drug development in almost three decades.…”

Unravelling the Role of Kinases That Underpin Androgen Signalling in Prostate Cancer

“…CDK8 and its analogue CDK19 regulate distinct gene profiles, and both may need to be inhibited for the optimum therapeutic benefit [182]. Indeed, several CDK8/CDK19 inhibitors are in preclinical development, and one-BCD-115-has completed Phase I clinical trials (Trial identifier: NCT03065010), although the results have not yet been posted [198]. Recently, Ma et al reviewed the binding profiles of 24 CDK8 inhibitors and highlighted four methods of identifying new inhibitors, which may be more selective for CDK8 [199].…”

From Structure Modification to Drug Launch: A Systematic Review of the Ongoing Development of Cyclin-Dependent Kinase Inhibitors for Multiple Cancer Therapy

“…Zhang et al 13 summarized the preclinical pharmacological and clinical effects of some pan-CDK inhibitors and selective CDK inhibitors. Bhurta et al 14 analyzed the scaffold diversity of CDK inhibitors. Łukasik et al 15 reviewed the representative ATP-competitive CDK inhibitors and allosteric inhibitors in active development.…”