6CCY

Crystal structure of Akt1 in complex with a selective inhibitor

Summary for 6CCY

• Entry DOI: 10.2210/pdb6ccy/pdb
• Descriptor: RAC-alpha serine/threonine-protein kinase,PIFtide, (5R)-4-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[2-(pyrrolidin-1-yl)ethyl]-1H-imidazol-2-yl}piperidin-1-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (3 entities in total)
• Functional Keywords: kinase inhibitor, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Cytoplasm : Q16513
• Total number of polymer chains: 1
• Total formula weight: 40530.12

Authors

Wang, Y.,Stout, S. (deposition date: 2018-02-07, release date: 2018-05-02, Last modification date: 2024-11-20)

Primary citation

Parthasarathy, S.,Henry, K.,Pei, H.,Clayton, J.,Rempala, M.,Johns, D.,De Frutos, O.,Garcia, P.,Mateos, C.,Pleite, S.,Wang, Y.,Stout, S.,Condon, B.,Ashok, S.,Lu, Z.,Ehlhardt, W.,Raub, T.,Lai, M.,Geeganage, S.,Burkholder, T.P.
Discovery of chiral dihydropyridopyrimidinones as potent, selective and orally bioavailable inhibitors of AKT.
Bioorg. Med. Chem. Lett., 28:1887-1891, 2018

PubMed Abstract: During the course of our research efforts to develop potent and selective AKT inhibitors, we discovered enatiomerically pure substituted dihydropyridopyrimidinones (DHP) as potent inhibitors of protein kinase B/AKT with excellent selectivity against ROCK. A key challenge in this program was the poor physicochemical properties of the initial lead compound 5. Integration of structure-based drug design and physical properties-based design resulted in replacement of a highly hydrophobic poly fluorinated aryl ring by a simple trifluoromethyl that led to identification of compound 6 with much improved physicochemical properties. Subsequent SAR studies led to the synthesis of new pyran analog 7 with improved cell potency. Further optimization of pharmacokintetics properties by increasing permeability with appropriate fluorinated alkyl led to compound 8 as a potent, selective AKT inhibitors that blocks the phosphorylation of GSK3β in vivo and had robust, dose and concentration dependent efficacy in the U87MG tumor xenograft model.

PubMed: 29655979
DOI: 10.1016/j.bmcl.2018.03.092

Experimental method

X-RAY DIFFRACTION (2.18 Å)