Structure-Based Optimization of Potent, Selective, and Orally Bioavailable CDK8 Inhibitors Discovered by High-Throughput Screening.

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ICR Authors

Raynaud, Florence
 Clarke, Paul

Authors

Czodrowski, P
Mallinger, A
Wienke, D
Esdar, C
Pöschke, O
Busch, M
Rohdich, F
Eccles, SA
Ortiz-Ruiz, M-J
Schneider, R
Raynaud, FI
Clarke, PA
Musil, D
Schwarz, D
Dale, T
Urbahns, K
Blagg, J
Schiemann, K

Document Type

Journal Article

Date

2016-10-27

Date Accepted

2016-08-05

Abstract

The mediator complex-associated cyclin dependent kinase CDK8 regulates β-catenin-dependent transcription following activation of WNT signaling. Multiple lines of evidence suggest CDK8 may act as an oncogene in the development of colorectal cancer. Here we describe the successful optimization of an imidazo-thiadiazole series of CDK8 inhibitors that was identified in a high-throughput screening campaign and further progressed by structure-based design. In several optimization cycles, we improved the microsomal stability, potency, and kinase selectivity. The initial imidazo-thiadiazole scaffold was replaced by a 3-methyl-1H-pyrazolo[3,4-b]-pyridine which resulted in compound 25 (MSC2530818) that displayed excellent kinase selectivity, biochemical and cellular potency, microsomal stability, and is orally bioavailable. Furthermore, we demonstrated modulation of phospho-STAT1, a pharmacodynamic biomarker of CDK8 activity, and tumor growth inhibition in an APC mutant SW620 human colorectal carcinoma xenograft model after oral administration. Compound 25 demonstrated suitable potency and selectivity to progress into preclinical in vivo efficacy and safety studies.

Citation

Journal of medicinal chemistry, 2016, 59 (20), pp. 9337 - 9349

DOI

10.1021/acs.jmedchem.6b00597

URI

https://repository.icr.ac.uk/handle/internal/266

Rights

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

Source Title

Publisher

AMER CHEMICAL SOC

ISSN

0022-2623

eISSN

1520-4804

Collections

Cancer Therapeutics

Research Team

Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 1
Signal Transduction & Molecular Pharmacology

Notes