Design of selective PI3Kδ inhibitors using an iterative scaffold-hopping workflow.

Binding Sites / drug effects Dose-Response Relationship, Drug Drug Design Humans Molecular Structure Oxindoles / chemical synthesis Phosphatidylinositol 3-Kinases / metabolism Phosphoinositide-3 Kinase Inhibitors / chemical synthesis Structure-Activity Relationship
Oxindole PI3Kδ Scaffold-hopping Structure-based drug design

Journal

Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377

Informations de publication

Date de publication:
15 09 2019
Historique:
received: 06 06 2019
revised: 01 08 2019
accepted: 02 08 2019
pubmed: 17 8 2019
medline: 21 10 2020
entrez: 17 8 2019
Statut: ppublish

Résumé

PI3Kδ mediates key immune cell signaling pathways and is a target of interest for multiple indications in immunology and oncology. Here we report a structure-based scaffold-hopping strategy for the design of chemically diverse PI3Kδ inhibitors. Using this strategy, we identified several scaffolds that can be combined to generate new PI3Kδ inhibitors with high potency and isoform selectivity. In particular, an oxindole-based scaffold was found to impart exquisite selectivity when combined with several hinge binding motifs.

Identifiants

DOI: 10.1016/j.bmcl.2019.08.004 PMID: 31416665
pubmed: 31416665
pii: S0960-894X(19)30530-X
doi: 10.1016/j.bmcl.2019.08.004
pii:
doi:

Substances chimiques

Oxindoles 0
Phosphoinositide-3 Kinase Inhibitors 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

2575-2580

Commentaires et corrections

Type : ErratumIn

Informations de copyright

Copyright © 2019 Elsevier Ltd. All rights reserved.

Auteurs

Xavier Fradera (X)

Computational and Structural Chemistry, Merck & Co., Inc., Boston, MA, USA. Electronic address: xavier.fradera@merck.com.

Joey L Methot (JL)

Discovery Chemistry, Merck & Co., Inc., Boston, MA, USA.

Abdelghani Achab (A)

Discovery Chemistry, Merck & Co., Inc., Boston, MA, USA.

Matthew Christopher (M)

Discovery Chemistry, Merck & Co., Inc., Boston, MA, USA.

Michael D Altman (MD)

Computational and Structural Chemistry, Merck & Co., Inc., Boston, MA, USA.

Hua Zhou (H)

Discovery Chemistry, Merck & Co., Inc., Boston, MA, USA.

Meredeth A McGowan (MA)

Discovery Chemistry, Merck & Co., Inc., Boston, MA, USA.

Sam D Kattar (SD)

Discovery Chemistry, Merck & Co., Inc., Boston, MA, USA.

Kevin Wilson (K)

Discovery Chemistry, Merck & Co., Inc., Boston, MA, USA.

Yudith Garcia (Y)

Discovery Chemistry, Merck & Co., Inc., Boston, MA, USA.

Martin A Augustin (MA)

Proteros Biostructures GmbH, Martinsried, Germany.

Charles A Lesburg (CA)

Computational and Structural Chemistry, Merck & Co., Inc., Boston, MA, USA.

Sanjiv Shah (S)

In vitro Pharmacology, Merck & Co., Inc., Boston, MA, USA.

Peter Goldenblatt (P)

In vitro Pharmacology, Merck & Co., Inc., Boston, MA, USA.

Jason D Katz (JD)

Discovery Chemistry, Merck & Co., Inc., Boston, MA, USA.

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Classifications MeSH

questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Sites de fixation › Design of selective PI3Kδ inhibitors using an...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes toxicologiques › Relation dose-effet des médicaments › Design of selective PI3Kδ inhibitors using an...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Découverte de médicament › Conception de médicament › Design of selective PI3Kδ inhibitors using an...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Design of selective PI3Kδ inhibitors using an...
questionsmedicales.fr › Phénomènes chimiques › Structure moléculaire › Design of selective PI3Kδ inhibitors using an...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Indolizine › Indolizidines › Alcaloïdes indoliques › Oxindoles › Design of selective PI3Kδ inhibitors using an...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Phosphatidylinositol 3-kinases › Design of selective PI3Kδ inhibitors using an...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs des phosphoinositide-3 kinases › Design of selective PI3Kδ inhibitors using an...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Relation structure-activité › Design of selective PI3Kδ inhibitors using an...