2. Academic Validation
  3. Discovery of 5,7-Dihydro-6 H-pyrrolo[2,3- d]pyrimidin-6-ones as Highly Selective CDK2 Inhibitors

Discovery of 5,7-Dihydro-6 H-pyrrolo[2,3- d]pyrimidin-6-ones as Highly Selective CDK2 Inhibitors

  • ACS Med Chem Lett. 2022 Oct 6;13(11):1797-1804. doi: 10.1021/acsmedchemlett.2c00408.
Alexander Sokolsky 1,  Sarah Winterton 1,  Keith Kennedy 1,  Katherine Drake 1,  Kristine Stump 1,  Lu Huo 1,  Yvonne Lo 1,  Min Ye 1,  Maryanne Covington 1,  Sharon Diamond 1,  Yan-Ou Yang 1,  Sunkyu Kim 1,  Swamy Yeleswaram 1,  Liangxing Wu 1,  Wenqing Yao 1
Affiliations

Affiliation

  • 1 Incyte Research Institute, Incyte Corporation, 1801 Augustine Cut-off, Wilmington, Delaware 19803, United States.
PMID: 36385925 DOI: 10.1021/acsmedchemlett.2c00408
Abstract

A series of exceptionally selective CDK2 inhibitors are described. Starting from an HTS hit, we successfully scaffold hopped to a 5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one core structure, which imparted a promising initial selectivity within the CDK family. Extensive further SAR identified additional factors that drove selectivity to above 200× for CDKs 1/4/6/7/9. General kinome selectivity was also greatly improved. Finally, use of in vivo metabolite identification allowed us to pinpoint sulfonamide dealkylation as the primary metabolite, which was ameliorated through the deuterium effect.

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