4o0r

Back pocket flexibility provides group-II PAK selectivity for type 1 kinase inhibitorsBack pocket flexibility provides group-II PAK selectivity for type 1 kinase inhibitors

Structural highlights

4o0r is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.4Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

Structure-based methods were used to design a potent and highly selective group II p21-activated kinase (PAK) inhibitor with a novel binding mode, compound 17. Hydrophobic interactions within a lipophilic pocket past the methionine gatekeeper of group II PAKs approached by these type I 1/2 binders were found to be important for improving potency. A structure-based hypothesis and strategy for achieving selectivity over group I PAKs, and the broad kinome, based on unique flexibility of this lipophilic pocket, is presented. A concentration-dependent decrease in tumor cell migration and invasion in two triple-negative breast cancer cell lines was observed with compound 17.

Back Pocket Flexibility Provides Group II p21-Activated Kinase (PAK) Selectivity for Type I 1/2 Kinase Inhibitors.,Staben ST, Feng JA, Lyle K, Belvin M, Boggs J, Burch JD, Chua CC, Cui H, Dipasquale AG, Friedman LS, Heise C, Koeppen H, Kotey A, Mintzer R, Oh A, Roberts DA, Rouge L, Rudolph J, Tam C, Wang W, Xiao Y, Young A, Zhang Y, Hoeflich KP J Med Chem. 2014 Feb 4. PMID:24432870^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Staben ST, Feng JA, Lyle K, Belvin M, Boggs J, Burch JD, Chua CC, Cui H, Dipasquale AG, Friedman LS, Heise C, Koeppen H, Kotey A, Mintzer R, Oh A, Roberts DA, Rouge L, Rudolph J, Tam C, Wang W, Xiao Y, Young A, Zhang Y, Hoeflich KP. Back Pocket Flexibility Provides Group II p21-Activated Kinase (PAK) Selectivity for Type I 1/2 Kinase Inhibitors. J Med Chem. 2014 Feb 4. PMID:24432870 doi:http://dx.doi.org/10.1021/jm401768t

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OCA

[1] Staben ST, Feng JA, Lyle K, Belvin M, Boggs J, Burch JD, Chua CC, Cui H, Dipasquale AG, Friedman LS, Heise C, Koeppen H, Kotey A, Mintzer R, Oh A, Roberts DA, Rouge L, Rudolph J, Tam C, Wang W, Xiao Y, Young A, Zhang Y, Hoeflich KP. Back Pocket Flexibility Provides Group II p21-Activated Kinase (PAK) Selectivity for Type I 1/2 Kinase Inhibitors. J Med Chem. 2014 Feb 4. PMID:24432870 doi:http://dx.doi.org/10.1021/jm401768t

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