2. Academic Validation
  3. 2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19

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.
Aurélie Mallinger 1,  Kai Schiemann 2,  Christian Rink 1,  Jimmy Sejberg 1,  Mark A Honey 1,  Paul Czodrowski 2,  Mark Stubbs 1,  Oliver Poeschke 2,  Michael Busch 2,  Richard Schneider 2,  Daniel Schwarz 2,  Djordje Musil 2,  Rosemary Burke 1,  Klaus Urbahns 2,  Paul Workman 1,  Dirk Wienke 2,  Paul A Clarke 1,  Florence I Raynaud 1,  Suzanne A Eccles 1,  Christina Esdar 2,  Felix Rohdich 2,  Julian Blagg 1
Affiliations

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 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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