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
  • 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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