Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 7, Issue 6, Pages 573-578Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.6b00022
Keywords
CDK8; CDK19; mediator complex; kinase inhibitor; aldehyde oxidase
Categories
Funding
- Cancer Research UK [C309/A11566]
- NHS
- Royal Marsden
- Cancer Research UK [11566] Funding Source: researchfish
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We demonstrate a designed scaffold-hop approach to the discovery of 2,8-disubstituted-1,6-naphthyridine- and 4,6-disubstituted-isoquinoline-based dual CDK8/19 ligands. Optimized compounds in both series exhibited rapid aldehyde oxidase-mediated metabolism, which could be abrogated by introduction of an amino substituent at C5 of the 1,6-naphthyridine scaffold or at C1 of the isoquinoline scaffold. Compounds 51 and 59 were progressed to in vivo pharmacokinetic studies, and 51 also demonstrated sustained inhibition of STAT1(SER727) phosphorylation, a biomarker of CDK8 inhibition, in an SW620 colorectal carcinoma human tumor xenograft model following oral dosing.
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