| Structural highlights
3qcx is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | 3Q2, GOL, SO4
| | NonStd Res: | SEP |
| Related: | 3nun, 3nus, 3nuu, 3nuy, 3qcq, 3qcs, 3qcy, 3qd0, 3qd3, 3qd4 |
| Gene: | PDK1, PDPK1 (Homo sapiens) |
| Activity: | Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Publication Abstract from PubMed
Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.
Structure-Based Design of Potent and Selective 3-Phosphoinositide-Dependent Kinase-1 (PDK1) Inhibitors.,Medina JR, Becker CJ, Blackledge CW, Duquenne C, Feng Y, Grant SW, Heerding D, Li WH, Miller WH, Romeril SP, Scherzer D, Shu A, Bobko MA, Chadderton AR, Dumble M, Gardiner CM, Gilbert S, Liu Q, Rabindran SK, Sudakin V, Xiang H, Brady PG, Campobasso N, Ward P, Axten JM J Med Chem. 2011 Feb 22. PMID:21341675[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See AlsoReferences
- ↑ Medina JR, Becker CJ, Blackledge CW, Duquenne C, Feng Y, Grant SW, Heerding D, Li WH, Miller WH, Romeril SP, Scherzer D, Shu A, Bobko MA, Chadderton AR, Dumble M, Gardiner CM, Gilbert S, Liu Q, Rabindran SK, Sudakin V, Xiang H, Brady PG, Campobasso N, Ward P, Axten JM. Structure-Based Design of Potent and Selective 3-Phosphoinositide-Dependent Kinase-1 (PDK1) Inhibitors. J Med Chem. 2011 Feb 22. PMID:21341675 doi:10.1021/jm101527u
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