3RWQ: Discovery Of A Novel, Potent And Selective Inhibitor Of 3- Phosphoinositide Dependent Kinase (Pdk1)

Analogues substituted with various amines at the 6-position of the pyrazine ring on (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrazin-2-ylmethanone were discovered as potent and selective inhibitors of PDK1 with potential as anticancer agents. An early lead with 2-pyridine-3-ylethylamine as the pyrazine substituent showed moderate potency and selectivity. Structure-based drug design led to improved potency and selectivity against PI3Kalpha through a combination of cyclizing the ethylene spacer into a saturated, five-membered ring and substituting on the 4-position of the aryl ring with a fluorine. ADME properties were improved by lowering the lipophilicity with heteroatom replacements in the saturated, five-membered ring. The optimized analogues have a PDK1 K(i) of 1 nM and >100-fold selectivity against PI3K/AKT-pathway kinases. The cellular potency of these analogues was assessed by the inhibition of AKT phosphorylation (T308) and by their antiproliferation activity against a number of tumor cell lines.
PDB ID: 3RWQDownload
MMDB ID: 95050
PDB Deposition Date: 2011/5/9
Updated in MMDB: 2011/12
Experimental Method:
x-ray diffraction
Resolution: 2.55  Å
Source Organism:
Similar Structures:
Biological Unit for 3RWQ: monomeric; determined by author
Molecular Components in 3RWQ
Label Count Molecule
Protein (1 molecule)
3-phosphoinositide-dependent Protein Kinase 1(Gene symbol: PDPK1)
Molecule annotation
Chemicals (11 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB