Development of Dual and Selective Degraders of Cyclin‐Dependent Kinases 4 and 6. (29th March 2019)

• Record Type: Journal Article
• Authors: Jiang, Baishan; Wang, Eric S.; Donovan, Katherine A.; Liang, Yanke; Fischer, Eric S.; Zhang, Tinghu; Gray, Nathanael S.
• Is Part Of: Angewandte Chemie. Volume 131:Number 19(2019)
• Page Start: 6387
• Page End: 6392
• Publication Date: 2019-03-29
• Subjects: CDK4/6 -- Krebs -- Proteinabbau -- Wirkstoffentwicklung -- Zellzyklus; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201901336
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: Cyclin‐dependent kinases 4 and 6 (CDK4/6) are key regulators of the cell cycle, and there are FDA‐approved CDK4/6 inhibitors for treating patients with metastatic breast cancer. However, due to conservation of their ATP‐binding sites, development of selective agents has remained elusive. Here, we report imide‐based degrader molecules capable of degrading both CDK4/6, or selectively degrading either CDK4 or CDK6. We were also able to tune the activity of these molecules against Ikaros (IKZF1) and Aiolos (IKZF3), which are well‐established targets of imide‐based degraders. We found that in mantle cell lymphoma cell lines, combined IKZF1/3 degradation with dual CDK4/6 degradation produced enhanced anti‐proliferative effects compared to CDK4/6 inhibition, CDK4/6 degradation, or IKZF1/3 degradation. In summary, we report here the first compounds capable of inducing selective degradation of CDK4 and CDK6 as tools to pharmacologically dissect their distinct biological functions. Abstract : Ziel zerstört : Inhibitoren der Cyclin‐abhängigen Kinasen 4 und 6 (CDK4/6) können nicht zwischen den beiden Proteinen unterscheiden. Allerdings ergab die Umwandlung von Inhibitoren in kleine Protein‐abbauende Moleküle Verbindungen, die zur schnellen, wirksamen und selektiven Eliminierung von nur CDK4, nur CDK6 oder beidem in der Lage sind. Diese neuartigen chemischen Sonden können bei der Aufklärung der homologspezifischen Funktionen von CDK4/6 helfen.