Development of BET inhibitors as potential treatments for cancer: A search for structural diversity.

Animals Antineoplastic Agents / chemical synthesis Carbolines / chemical synthesis Dose-Response Relationship, Drug Drug Development Humans Mice Molecular Structure Multiple Myeloma / diet therapy Proteins / antagonists & inhibitors Structure-Activity Relationship Triazoles / chemical synthesis
BET Bromodomain Cancer Lipophilic ligand efficiency Multiple myeloma

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 07 2021
Historique:
received: 12 03 2021
revised: 05 05 2021
accepted: 09 05 2021
pubmed: 16 5 2021
medline: 6 1 2022
entrez: 15 5 2021
Statut: ppublish

Résumé

We describe our efforts to identify structurally diverse leads in the triazole-containing N1-carboline series of bromodomain and extra-terminal inhibitors. Replacement of the N5 "cap" phenyl moiety with various heteroaryls, coupled with additional modifications to the carboline core, provided analogs with similar potency, improved pharmacokinetic properties, and increased solubility compared to our backup lead, BMS-986225 (2). Rapid SAR exploration was enabled by a convergent, synthetic route. These efforts provided a potent BET inhibitor, 3-fluoropyridyl 12, that demonstrated robust efficacy in a multiple myeloma mouse tumor model at 1 mg/kg.

Identifiants

DOI: 10.1016/j.bmcl.2021.128108 PMID: 33991625
pubmed: 33991625
pii: S0960-894X(21)00334-6
doi: 10.1016/j.bmcl.2021.128108
pii:
doi:

Substances chimiques

Antineoplastic Agents 0
Carbolines 0
Proteins 0
Triazoles 0
bromodomain and extra-terminal domain protein, human 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

128108

Informations de copyright

Copyright © 2021 Elsevier Ltd. All rights reserved.

Auteurs

Matthew D Hill (MD)

Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA. Electronic address: matthew.hill@bms.com.

Haiquan Fang (H)

Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.

John Tokarski (J)

Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.

Carolynn Fanslau (C)

Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.

Zuzana Haarhoff (Z)

Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.

Christine Huang (C)

Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.

Melissa Kramer (M)

Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.

Krista Menard (K)

Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.

Laura Monereau (L)

Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.

John Morrison (J)

Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.

Asoka Ranasinghe (A)

Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.

Eric E Shields (EE)

Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.

Ching Kim Tye (CK)

Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.

Richard Westhouse (R)

Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.

Gerry Everlof (G)

Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.

Steven Sheriff (S)

Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.

Chunhong Yan (C)

Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.

Frank Marsilio (F)

Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.

Lisa Zhang (L)

Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.

Tatyana Zvyaga (T)

Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.

Francis Lee (F)

Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.

Ashvinikumar V Gavai (AV)

Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.

Andrew P Degnan (AP)

Bristol Myers Squibb Research and Development, 100 Binney St, Cambridge, MA 02142-1096, USA.

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Development of BET inhibitors as potential...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › Development of BET inhibitors as potential...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérocycliques 3 noyaux › Carbolines › Development of BET inhibitors as potential...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes toxicologiques › Relation dose-effet des médicaments › Development of BET inhibitors as potential...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Development of BET inhibitors as potential...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Development of BET inhibitors as potential...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Development of BET inhibitors as potential...
questionsmedicales.fr › Phénomènes chimiques › Structure moléculaire › Development of BET inhibitors as potential...
questionsmedicales.fr › Maladies du système immunitaire › Syndromes immunoprolifératifs › Paraprotéinémies › Myélome multiple › Development of BET inhibitors as potential...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Development of BET inhibitors as potential...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Relation structure-activité › Development of BET inhibitors as potential...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Azoles › Triazoles › Development of BET inhibitors as potential...