Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19.

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ICR Authors

Burke, Rosemary
 Workman, Paul
 Clarke, Paul
 Raynaud, Florence
 Eccles, Suzanne

Authors

Mallinger, A
Schiemann, K
Rink, C
Stieber, F
Calderini, M
Crumpler, S
Stubbs, M
Adeniji-Popoola, O
Poeschke, O
Busch, M
Czodrowski, P
Musil, D
Schwarz, D
Ortiz-Ruiz, M-J
Schneider, R
Thai, C
Valenti, M
de Haven Brandon, A
Burke, R
Workman, P
Dale, T
Wienke, D
Clarke, PA
Esdar, C
Raynaud, FI
Eccles, SA
Rohdich, F
Blagg, J

Document Type

Journal Article

Date

2016-02-11

Date Accepted

Abstract

The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 (CCT251921), a potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19. We describe a structure-based design approach leading to the discovery of a 3,4,5-trisubstituted-2-aminopyridine series and present the application of physicochemical property analyses to successfully reduce in vivo metabolic clearance, minimize transporter-mediated biliary elimination while maintaining acceptable aqueous solubility. Compound 109 affords the optimal compromise of in vitro biochemical, pharmacokinetic, and physicochemical properties and is suitable for progression to animal models of cancer.

Citation

Journal of medicinal chemistry, 2016, 59 (3), pp. 1078 - 1101

DOI

10.1021/acs.jmedchem.5b01685

URI

https://repository.icr.ac.uk/handle/internal/3774

Rights

https://creativecommons.org/licenses/by/4.0

Source Title

Publisher

AMER CHEMICAL SOC

ISSN

0022-2623

eISSN

1520-4804

Collections

Cancer Therapeutics
Structural Biology

Research Team

Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 1
Signal Transduction & Molecular Pharmacology
Tumour Biology & Metastasis
Hit Discovery & Structural Design

Notes