4WAF

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

Summary for 4WAF

• Entry DOI: 10.2210/pdb4waf/pdb
• Descriptor: 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)
• Functional Keywords: pi3k, chimera, lipid kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 164306.65

Authors

Knapp, M.S.,Elling, R.A. (deposition date: 2014-08-29, release date: 2014-12-31, Last modification date: 2023-09-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.39 Å)