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Mallinger A, Schiemann K, Rink C, et al. 2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19. ACS Med Chem Lett. 2016;7(6):573-8doi: 10.1021/acsmedchemlett.6b00022.
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. (2016). 2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19. ACS medicinal chemistry letters, 7(6), 573-8. https://doi.org/10.1021/acsmedchemlett.6b00022
Mallinger, Aurélie, et al. "2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19." ACS medicinal chemistry letters vol. 7,6 (2016): 573-8. doi: https://doi.org/10.1021/acsmedchemlett.6b00022
Mallinger A, Schiemann K, Rink C, Sejberg J, Honey MA, Czodrowski P, Stubbs M, Poeschke O, Busch M, Schneider R, Schwarz D, Musil D, Burke R, Urbahns K, Workman P, Wienke D, Clarke PA, Raynaud FI, Eccles SA, 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. 2016 Mar 28;7(6):573-8. doi: 10.1021/acsmedchemlett.6b00022. eCollection 2016 Jun 09. PMID: 27326329; PMCID: PMC4904262.
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ACS Med Chem Lett. 2016 Mar 28;7(6):573-8. doi: 10.1021/acsmedchemlett.6b00022. eCollection 2016 Jun 09.

2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19.

ACS medicinal chemistry letters

Aurélie Mallinger, Kai Schiemann, Christian Rink, Jimmy Sejberg, Mark A Honey, Paul Czodrowski, Mark Stubbs, Oliver Poeschke, Michael Busch, Richard Schneider, Daniel Schwarz, Djordje Musil, Rosemary Burke, Klaus Urbahns, Paul Workman, Dirk Wienke, Paul A Clarke, Florence I Raynaud, Suzanne A Eccles, Christina Esdar, Felix Rohdich, Julian Blagg

Affiliations

  1. Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, UK.
  2. Merck KGaA, Darmstadt 64293, Germany.

PMID: 27326329 PMCID: PMC4904262 DOI: 10.1021/acsmedchemlett.6b00022

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.

Keywords: CDK19; CDK8; aldehyde oxidase; kinase inhibitor; mediator complex

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