| Structural highlights
4ez5 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: |
| | Related: | 3nup, 3nux |
| Gene: | CDK6, CDKN6 (HUMAN) |
| Activity: | Cyclin-dependent kinase, with EC number 2.7.11.22 |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Publication Abstract from PubMed
Herein, we describe the discovery of potent and highly selective inhibitors of both CDK4 and CDK6 via structure-guided optimization of a fragment-based screening hit. CDK6 X-ray crystallography and pharmacokinetic data steered efforts in identifying compound 6, which showed >1000-fold selectivity for CDK4 over CDKs 1 and 2 in an enzymatic assay. Furthermore, 6 demonstrated in vivo inhibition of pRb-phosphorylation and oral efficacy in a Jeko-1 mouse xenograft model.
Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors.,Cho YS, Angove H, Brain C, Chen CH, Cheng H, Cheng R, Chopra R, Chung K, Congreve M, Dagostin C, Davis DJ, Feltell R, Giraldes J, Hiscock SD, Kim S, Kovats S, Lagu B, Lewry K, Loo A, Lu Y, Luzzio M, Maniara W, McMenamin R, Mortenson PN, Benning R, O'Reilly M, Rees DC, Shen J, Smith T, Wang Y, Williams G, Woolford AJ, Wrona W, Xu M, Yang F, Howard S ACS Med Chem Lett. 2012 May 17;3(6):445-9. doi: 10.1021/ml200241a. eCollection, 2012 Jun 14. PMID:24900493[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Cho YS, Angove H, Brain C, Chen CH, Cheng H, Cheng R, Chopra R, Chung K, Congreve M, Dagostin C, Davis DJ, Feltell R, Giraldes J, Hiscock SD, Kim S, Kovats S, Lagu B, Lewry K, Loo A, Lu Y, Luzzio M, Maniara W, McMenamin R, Mortenson PN, Benning R, O'Reilly M, Rees DC, Shen J, Smith T, Wang Y, Williams G, Woolford AJ, Wrona W, Xu M, Yang F, Howard S. Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors. ACS Med Chem Lett. 2012 May 17;3(6):445-9. doi: 10.1021/ml200241a. eCollection, 2012 Jun 14. PMID:24900493 doi:http://dx.doi.org/10.1021/ml200241a
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