4WAF

Crystal Structure of a novel tetrahydropyrazolo[1,5-a]pyrazine in an engineered PI3K alpha

4WAF の概要

• エントリーDOI: 10.2210/pdb4waf/pdb
• 分子名称: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha, N,N-dimethyl-4-[(6R)-6-methyl-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]benzenesulfonamide, ... (4 entities in total)
• 機能のキーワード: pi3k, chimera, lipid kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 164306.65

構造登録者

Knapp, M.S.,Elling, R.A. (登録日: 2014-08-29, 公開日: 2014-12-31, 最終更新日: 2023-09-27)

主引用文献

Barsanti, P.A.,Aversa, R.J.,Jin, X.,Pan, Y.,Lu, Y.,Elling, R.,Jain, R.,Knapp, M.,Lan, J.,Lin, X.,Rudewicz, P.,Sim, J.,Taricani, L.,Thomas, G.,Xiao, L.,Yue, Q.
Structure-Based Drug Design of Novel Potent and Selective Tetrahydropyrazolo[1,5-a]pyrazines as ATR Inhibitors.
Acs Med.Chem.Lett., 6:37-41, 2015

PubMed Abstract: A saturation strategy focused on improving the selectivity and physicochemical properties of ATR inhibitor HTS hit 1 led to a novel series of highly potent and selective tetrahydropyrazolo[1,5-a]pyrazines. Use of PI3Kα mutants as ATR crystal structure surrogates was instrumental in providing cocrystal structures to guide the medicinal chemistry designs. Detailed DMPK studies involving cyanide and GSH as trapping agents during microsomal incubations, in addition to deuterium-labeled compounds as mechanistic probes uncovered the molecular basis for the observed CYP3A4 TDI in the series.

PubMed: 25589927
DOI: 10.1021/ml500353p

実験手法

X-RAY DIFFRACTION (2.39 Å)