4FHK

Crystal Structure of PI3K-gamma in Complex with Imidazopyridazine 19e

Summary for 4FHK

• Entry DOI: 10.2210/pdb4fhk/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, SULFATE ION, 3-[2-methyl-6-(pyrazin-2-ylamino)pyrimidin-4-yl]-N-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-amine, ... (4 entities in total)
• Functional Keywords: p110, kinase, atp-binding, p84, p101, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : P48736
• Total number of polymer chains: 1
• Total formula weight: 110593.69

Authors

Shaffer, P.L.,Tang, J.,Yakowec, P. (deposition date: 2012-06-06, release date: 2013-04-10, Last modification date: 2023-09-13)

Primary citation

Peterson, E.A.,Boezio, A.A.,Andrews, P.S.,Boezio, C.M.,Bush, T.L.,Cheng, A.C.,Choquette, D.,Coats, J.R.,Colletti, A.E.,Copeland, K.W.,DuPont, M.,Graceffa, R.,Grubinska, B.,Kim, J.L.,Lewis, R.T.,Liu, J.,Mullady, E.L.,Potashman, M.H.,Romero, K.,Shaffer, P.L.,Stanton, M.K.,Stellwagen, J.C.,Teffera, Y.,Yi, S.,Cai, T.,La, D.S.
Discovery and optimization of potent and selective imidazopyridine and imidazopyridazine mTOR inhibitors.
Bioorg.Med.Chem.Lett., 22:4967-4974, 2012

PubMed Abstract: mTOR is a critical regulator of cellular signaling downstream of multiple growth factors. The mTOR/PI3K/AKT pathway is frequently mutated in human cancers and is thus an important oncology target. Herein we report the evolution of our program to discover ATP-competitive mTOR inhibitors that demonstrate improved pharmacokinetic properties and selectivity compared to our previous leads. Through targeted SAR and structure-guided design, new imidazopyridine and imidazopyridazine scaffolds were identified that demonstrated superior inhibition of mTOR in cellular assays, selectivity over the closely related PIKK family and improved in vivo clearance over our previously reported benzimidazole series.

PubMed: 22765895
DOI: 10.1016/j.bmcl.2012.06.033

Experimental method

X-RAY DIFFRACTION (3 Å)