Structure-guided discovery of a novel, potent, and orally bioavailable 3,5-dimethylisoxazole aryl-benzimidazole BET bromodomain inhibitor.

Administration, Oral Animals Benzimidazoles / chemistry Biological Availability Cell Line, Tumor Cell Proliferation / drug effects Cell Survival / drug effects Dose-Response Relationship, Drug Drug Discovery Humans Isoxazoles / administration & dosage Mice Molecular Structure Multiple Myeloma / drug therapy Neoplasms, Experimental / drug therapy Protein Domains / drug effects Structure-Activity Relationship Transcription Factors / antagonists & inhibitors
Antitumor BET proteins Bromodomain inhibitor Epigenetic readers

Journal

Bioorganic & medicinal chemistry
ISSN: 1464-3391
Titre abrégé: Bioorg Med Chem
Pays: England
ID NLM: 9413298

Informations de publication

Date de publication:
01 02 2019
Historique:
received: 26 07 2018
revised: 05 11 2018
accepted: 13 11 2018
pubmed: 5 1 2019
medline: 18 12 2019
entrez: 5 1 2019
Statut: ppublish

Résumé

The bromodomain and extra-terminal (BET) family of proteins, consisting of the bromodomains containing protein 2 (BRD2), BRD3, BRD4, and the testis-specific BRDT, are key epigenetic regulators of gene transcription and has emerged as an attractive target for anticancer therapy. Herein, we describe the discovery of a novel potent BET bromodomain inhibitor, using a systematic structure-based approach focused on improving potency, metabolic stability, and permeability. The optimized dimethylisoxazole aryl-benzimidazole inhibitor exhibited high potency towards BRD4 and related BET proteins in biochemical and cell-based assays and inhibited tumor growth in two proof-of-concept preclinical animal models.

Identifiants

DOI: 10.1016/j.bmc.2018.11.020 PMID: 30606676
pubmed: 30606676
pii: S0968-0896(18)31356-7
doi: 10.1016/j.bmc.2018.11.020
pii:
doi:

Substances chimiques

Benzimidazoles 0
Isoxazoles 0
Transcription Factors 0

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

457-469

Subventions

Organisme : NIH HHS
ID : S10 OD021832
Pays : United States

Informations de copyright

Copyright © 2018 Elsevier Ltd. All rights reserved.

Auteurs

David Sperandio (D)

Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA. Electronic address: david.sperandio@r2mpharma.com.

Vangelis Aktoudianakis (V)

Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Kerim Babaoglu (K)

Department of Structural Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Xiaowu Chen (X)

Department of Structural Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Kristyna Elbel (K)

Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Gregory Chin (G)

Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Britton Corkey (B)

Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Jinfa Du (J)

Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Bob Jiang (B)

Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Tetsuya Kobayashi (T)

Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Richard Mackman (R)

Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Ruben Martinez (R)

Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Hai Yang (H)

Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Jeff Zablocki (J)

Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Saritha Kusam (S)

Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Kim Jordan (K)

Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Heather Webb (H)

Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Jamie G Bates (JG)

Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Latesh Lad (L)

Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Michael Mish (M)

Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Anita Niedziela-Majka (A)

Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Sammy Metobo (S)

Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Annapurna Sapre (A)

Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Magdeleine Hung (M)

Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Debi Jin (D)

Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Wanchi Fung (W)

Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Elaine Kan (E)

Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Gene Eisenberg (G)

Department of Drug Metabolism, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Nate Larson (N)

Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Zachary E R Newby (ZER)

Department of Structural Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Eric Lansdon (E)

Department of Structural Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Chin Tay (C)

Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Richard M Neve (RM)

Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

Sophia L Shevick (SL)

Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

David G Breckenridge (DG)

Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.

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Classifications MeSH

questionsmedicales.fr › Thérapeutique › Traitement médicamenteux › Voies d'administration de substances chimiques et des médicaments › Administration par voie orale › Structure-guided discovery of a novel, potent,...
questionsmedicales.fr › Eucaryotes › Animaux › Structure-guided discovery of a novel, potent,...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Benzimidazoles › Structure-guided discovery of a novel, potent,...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Pharmacocinétique › Biodisponibilité › Structure-guided discovery of a novel, potent,...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Structure-guided discovery of a novel, potent,...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › Structure-guided discovery of a novel, potent,...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Survie cellulaire › Structure-guided discovery of a novel, potent,...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes toxicologiques › Relation dose-effet des médicaments › Structure-guided discovery of a novel, potent,...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Découverte de médicament › Structure-guided discovery of a novel, potent,...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Structure-guided discovery of a novel, potent,...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Azoles › Isoxazoles › Structure-guided discovery of a novel, potent,...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Structure-guided discovery of a novel, potent,...
questionsmedicales.fr › Phénomènes chimiques › Structure moléculaire › Structure-guided discovery of a novel, potent,...
questionsmedicales.fr › Maladies du système immunitaire › Syndromes immunoprolifératifs › Paraprotéinémies › Myélome multiple › Structure-guided discovery of a novel, potent,...
questionsmedicales.fr › Techniques d'investigation › Modèles animaux › Tumeurs expérimentales › Structure-guided discovery of a novel, potent,...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Structure tertiaire des protéines › Domaines protéiques › Structure-guided discovery of a novel, potent,...
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questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Structure-guided discovery of a novel, potent,...