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2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19
Mallinger, Aurélie Schiemann, Kai Rink, Christian Sejberg, Jimmy Honey, Mark A. Czodrowski, Paul Stubbs, Mark Poeschke, Oliver Busch, Michael Schneider, Richard
Mallinger, Aurélie
Schiemann, Kai
Rink, Christian
Sejberg, Jimmy
Honey, Mark A.
Czodrowski, Paul
Stubbs, Mark
Poeschke, Oliver
Busch, Michael
Schneider, Richard
Authors
Mallinger, Aurélie
Schiemann, Kai
Rink, Christian
Sejberg, Jimmy
Honey, Mark A.
Czodrowski, Paul
Stubbs, Mark
Poeschke, Oliver
Busch, Michael
Schneider, Richard
Schwartz, Daniel
Musil, Djordje
Burke, Rosemary
Urbahns, Klaus
Workman, Paul
Wienke, Dirk
Clarke, Paul A.
Raynaud, Florence I.
Eccles, Suzanne A.
Esdar, Christina
Rohdich, Felix
Blagg, Julian
Schiemann, Kai
Rink, Christian
Sejberg, Jimmy
Honey, Mark A.
Czodrowski, Paul
Stubbs, Mark
Poeschke, Oliver
Busch, Michael
Schneider, Richard
Schwartz, Daniel
Musil, Djordje
Burke, Rosemary
Urbahns, Klaus
Workman, Paul
Wienke, Dirk
Clarke, Paul A.
Raynaud, Florence I.
Eccles, Suzanne A.
Esdar, Christina
Rohdich, Felix
Blagg, Julian
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2016-03-28
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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 STAT1SER727 phosphorylation, a biomarker of CDK8 inhibition, in an SW620 colorectal carcinoma human tumor xenograft model following oral dosing.
Citation
Mallinger, A., Schiemann, K., Rink, C. Sejberg, J, Honey, M. A. et. al. (2014) 2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19, ACS Medicinal Chemistry Letters, 7(6), pp. 573-578.
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Journal article
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en
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1948-5875
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Attribution-NonCommercial 3.0 United States