Free-Wilson Analysis of Comprehensive Data on Phosphoinositide-3-kinase (PI3K) Inhibitors Reveals Importance of

Amines / chemistry Humans Isoenzymes / chemistry Methylation Nitrogen / chemistry Phosphatidylinositol 3-Kinases / chemistry Phosphoinositide-3 Kinase Inhibitors / chemical synthesis Pyrimidines / chemistry Serum Albumin, Human / metabolism Structure-Activity Relationship

Journal

Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531

Informations de publication

Date de publication:
27 11 2019
Historique:
pubmed: 28 10 2019
medline: 15 7 2020
entrez: 25 10 2019
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1021/acs.jmedchem.9b01499 PMID: 31647659
pubmed: 31647659
doi: 10.1021/acs.jmedchem.9b01499
doi:

Substances chimiques

Amines 0
Isoenzymes 0
Phosphoinositide-3 Kinase Inhibitors 0
Pyrimidines 0
2-aminopyrimidine 109-12-6
Nitrogen N762921K75
Serum Albumin, Human ZIF514RVZR

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

10402-10422

Subventions

Organisme : Biotechnology and Biological Sciences Research Council
Pays : United Kingdom

Auteurs

Lydia Barnes (L)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Hollie Blaber (H)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

David T K Brooks (DTK)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Lewis Byers (L)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Daniel Buckley (D)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Zoe C Byron (ZC)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Richard G Chilvers (RG)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Liam Cochrane (L)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Edward Cooney (E)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Heather A Damian (HA)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Luke Francis (L)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Daniel Fu He (D)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Jack M J Grace (JMJ)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Harley J Green (HJ)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Edmund J P Hogarth (EJP)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Leyla Jusu (L)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

C Elizabeth Killalea (CE)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Oliver King (O)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Joseph Lambert (J)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Zoe J Lee (ZJ)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Nuria S Lima (NS)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Christina L Long (CL)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

May-Li Mackinnon (ML)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Shusha Mahdy (S)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Jolyon Matthews-Wright (J)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Makenzie J Millward (MJ)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Matthew F Meehan (MF)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Christopher Merrett (C)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Lisa Morrison (L)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Hal R I Parke (HRI)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Charlotte Payne (C)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Lawrence Payne (L)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Craig Pike (C)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Alexander Seal (A)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Aaron J Senior (AJ)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Keenan M Smith (KM)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Kamile Stanelyte (K)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Joe Stillibrand (J)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Rachel Szpara (R)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Freya F H Taday (FFH)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Antony M Threadgould (AM)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Rohan J Trainor (RJ)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Jordan Waters (J)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Oliver Williams (O)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Carrie K W Wong (CKW)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Katherine Wood (K)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.

Nick Barton (N)

GlaxoSmithKline, Medicines Research Centre , Gunnels Wood Road , Stevenage SG1 2NY , U.K.

Anna Gruszka (A)

GlaxoSmithKline, Medicines Research Centre , Gunnels Wood Road , Stevenage SG1 2NY , U.K.

Zoe Henley (Z)

GlaxoSmithKline, Medicines Research Centre , Gunnels Wood Road , Stevenage SG1 2NY , U.K.
ORCID: 0000-0001-6686-3210

James E Rowedder (JE)

GlaxoSmithKline, Medicines Research Centre , Gunnels Wood Road , Stevenage SG1 2NY , U.K.

Rosa Cookson (R)

GlaxoSmithKline, Medicines Research Centre , Gunnels Wood Road , Stevenage SG1 2NY , U.K.

Katherine L Jones (KL)

GlaxoSmithKline, Medicines Research Centre , Gunnels Wood Road , Stevenage SG1 2NY , U.K.

Alan Nadin (A)

GlaxoSmithKline, Medicines Research Centre , Gunnels Wood Road , Stevenage SG1 2NY , U.K.

Ian E Smith (IE)

GlaxoSmithKline, Medicines Research Centre , Gunnels Wood Road , Stevenage SG1 2NY , U.K.

Simon J F Macdonald (SJF)

GlaxoSmithKline, Medicines Research Centre , Gunnels Wood Road , Stevenage SG1 2NY , U.K.

Andrew Nortcliffe (A)

GlaxoSmithKline Carbon Neutral Laboratories for Sustainable Chemistry, School of Chemistry , University of Nottingham , Triumph Road , Nottingham NG7 2TU , U.K.
ORCID: 0000-0002-3371-390X

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Classifications MeSH

Recherchemedicale.com › Composés chimiques organiques › Amines › Free-Wilson Analysis of Comprehensive Data on...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Free-Wilson Analysis of Comprehensive Data on...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Isoformes de protéines › Isoenzymes › Free-Wilson Analysis of Comprehensive Data on...
Recherchemedicale.com › Métabolisme › Alkylation › Méthylation › Free-Wilson Analysis of Comprehensive Data on...
Recherchemedicale.com › Produits chimiques inorganiques › Gaz › Azote › Free-Wilson Analysis of Comprehensive Data on...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Phosphatidylinositol 3-kinases › Free-Wilson Analysis of Comprehensive Data on...
Recherchemedicale.com › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs des phosphoinositide-3 kinases › Free-Wilson Analysis of Comprehensive Data on...
Recherchemedicale.com › Composés hétérocycliques › Composés hétéromonocycliques › Pyrimidines › Free-Wilson Analysis of Comprehensive Data on...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines du sang › Sérumalbumine › Sérum-albumine humaine › Free-Wilson Analysis of Comprehensive Data on...
Recherchemedicale.com › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Relation structure-activité › Free-Wilson Analysis of Comprehensive Data on...