Free-Wilson Analysis of Comprehensive Data on Phosphoinositide-3-kinase (PI3K) Inhibitors Reveals Importance of N -Methylation for PI3Kδ Activity.

Autor: Barnes L; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Blaber H; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Brooks DTK; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Byers L; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Buckley D; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Byron ZC; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Chilvers RG; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Cochrane L; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Cooney E; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Damian HA; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Francis L; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Fu He D; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Grace JMJ; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Green HJ; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Hogarth EJP; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Jusu L; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Killalea CE; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., King O; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Lambert J; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Lee ZJ; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Lima NS; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Long CL; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Mackinnon ML; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Mahdy S; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Matthews-Wright J; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Millward MJ; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Meehan MF; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Merrett C; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Morrison L; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Parke HRI; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Payne C; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Payne L; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Pike C; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Seal A; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Senior AJ; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Smith KM; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Stanelyte K; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Stillibrand J; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Szpara R; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Taday FFH; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Threadgould AM; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Trainor RJ; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Waters J; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Williams O; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Wong CKW; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Wood K; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K., Barton N; GlaxoSmithKline, Medicines Research Centre , Gunnels Wood Road , Stevenage SG1 2NY , U.K., Gruszka A; GlaxoSmithKline, Medicines Research Centre , Gunnels Wood Road , Stevenage SG1 2NY , U.K., Henley Z; GlaxoSmithKline, Medicines Research Centre , Gunnels Wood Road , Stevenage SG1 2NY , U.K., Rowedder JE; GlaxoSmithKline, Medicines Research Centre , Gunnels Wood Road , Stevenage SG1 2NY , U.K., Cookson R; GlaxoSmithKline, Medicines Research Centre , Gunnels Wood Road , Stevenage SG1 2NY , U.K., Jones KL; GlaxoSmithKline, Medicines Research Centre , Gunnels Wood Road , Stevenage SG1 2NY , U.K., Nadin A; GlaxoSmithKline, Medicines Research Centre , Gunnels Wood Road , Stevenage SG1 2NY , U.K., Smith IE; GlaxoSmithKline, Medicines Research Centre , Gunnels Wood Road , Stevenage SG1 2NY , U.K., Macdonald SJF; GlaxoSmithKline, Medicines Research Centre , Gunnels Wood Road , Stevenage SG1 2NY , U.K., Nortcliffe A; GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2019 Nov 27; Vol. 62 (22), pp. 10402-10422. Date of Electronic Publication: 2019 Nov 06.
DOI: 10.1021/acs.jmedchem.9b01499
Abstrakt: Phosphoinositide-3-kinase δ (PI3Kδ) is a critical regulator of cell growth and transformation and has been explored as a therapeutic target for a range of diseases. Through the exploration of the thienopyrimidine scaffold, we have identified a ligand-efficient methylation that leads to remarkable selectivity for PI3Kδ over the closely related isoforms. Interrogation through the Free-Wilson analysis highlights the innate selectivity the thienopyrimidine scaffold has for PI3Kδ and provides a predictive model for the activity against the PI3K isoforms.
Databáze: MEDLINE