4FHK

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

4FHK の概要

• エントリーDOI: 10.2210/pdb4fhk/pdb
• 分子名称: 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)
• 機能のキーワード: p110, kinase, atp-binding, p84, p101, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm : P48736
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 110593.69

構造登録者

Shaffer, P.L.,Tang, J.,Yakowec, P. (登録日: 2012-06-06, 公開日: 2013-04-10, 最終更新日: 2023-09-13)

主引用文献

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

実験手法

X-RAY DIFFRACTION (3 Å)