3QCS: Phosphoinositide-Dependent Kinase-1 (PDK1) kinase domain with 6-[2-Amino-6-(4-morpholinyl)-4-pyrimidinyl]-1H-indazol-3-amine

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.
PDB ID: 3QCSDownload
MMDB ID: 89102
PDB Deposition Date: 2011/1/17
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 2.487  Å
Source Organism:
Similar Structures:
Biological Unit for 3QCS: monomeric; determined by author
Molecular Components in 3QCS
Label Count Molecule
Protein (1 molecule)
3-phosphoinositide-dependent Protein Kinase 1(Gene symbol: PDPK1)
Molecule annotation
Chemicals (10 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB