5I5Z

CDK8-CYCC IN COMPLEX WITH 8-(1-Methyl-2,2-dioxo-2,3-dihydro-1H-2l6-benzo[c]isothiazol-5-yl)-[1,6]naphthyridine-2-carboxylic acid methylamide

Summary for 5I5Z

• Entry DOI: 10.2210/pdb5i5z/pdb
• Descriptor: Cyclin-dependent kinase 8, Cyclin-C, N-methyl-8-(1-methyl-2,2-dioxo-2,3-dihydro-1H-2lambda~6~,1-benzothiazol-5-yl)-1,6-naphthyridine-2-carboxamide, ... (5 entities in total)
• Functional Keywords: cdk8 kinase / cyclin c, transferase
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : P49336 P24863
• Total number of polymer chains: 2
• Total formula weight: 75234.62

Authors

Musil, D.,Blagg, J.,Mallinger, A. (deposition date: 2016-02-15, release date: 2016-04-13, Last modification date: 2024-01-10)

Primary citation

Mallinger, A.,Schiemann, K.,Rink, C.,Sejberg, J.,Honey, M.A.,Czodrowski, P.,Stubbs, M.,Poeschke, O.,Busch, M.,Schneider, R.,Schwarz, D.,Musil, D.,Burke, R.,Urbahns, K.,Workman, P.,Wienke, D.,Clarke, P.A.,Raynaud, F.I.,Eccles, S.A.,Esdar, C.,Rohdich, F.,Blagg, J.
2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19.
Acs Med.Chem.Lett., 7:573-578, 2016

PubMed Abstract: 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.

PubMed: 27326329
DOI: 10.1021/acsmedchemlett.6b00022

Experimental method

X-RAY DIFFRACTION (2.6 Å)