5HBH: Cdk8-cycc In Complex With 5-{5-chloro-4-[1-(2-methoxy-ethyl)-1,8- Diaza-spiro[4.5]dec-8-yl]-pyridin-3-yl}-1-methyl-1,3-dihydro- Benzo[c]isothiazole 2,2-dioxide

Citation:
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.
PDB ID: 5HBHDownload
MMDB ID: 136297
PDB Deposition Date: 2015/12/31
Updated in MMDB: 2016/02
Experimental Method:
x-ray diffraction
Resolution: 2.5  Å
Source Organism:
Similar Structures:
Biological Unit for 5HBH: dimeric; determined by author and by software (PISA)
Molecular Components in 5HBH
Label Count Molecule
Proteins (2 molecules)
1
Cyclin-dependent Kinase 8(Gene symbol: CDK8)
Molecule annotation
1
Cyclin-c(Gene symbol: CCNC)
Molecule annotation
Chemicals (5 molecules)
1
1
2
1
3
3
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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