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

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

  • J Med Chem. 2016 Oct 27;59(20):9337-9349. doi: 10.1021/acs.jmedchem.6b00597.
Paul Czodrowski 1,  Aurélie Mallinger 2,  Dirk Wienke 1,  Christina Esdar 1,  Oliver Pöschke 1,  Michael Busch 1,  Felix Rohdich 1,  Suzanne A Eccles 2,  Maria-Jesus Ortiz-Ruiz 2,  Richard Schneider 1,  Florence I Raynaud 2,  Paul A Clarke 2,  Djordje Musil 1,  Daniel Schwarz 1,  Trevor Dale 3,  Klaus Urbahns 1,  Julian Blagg 2,  Kai Schiemann 1
Affiliations

Affiliations

  • 1 Merck KGaA , Frankfurter Strasse 250, Darmstadt, 64293, Germany.
  • 2 Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London, SW7 3RP, U.K.
  • 3 School of Bioscience, Cardiff University , Cardiff, CF10 3AX, U.K.
PMID: 27490956 DOI: 10.1021/acs.jmedchem.6b00597
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-101611
    99.62%, CDK8 抑制剂
    CDK
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z