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Discovery and Preclinical Pharmacology of an Oral Bromodomain and Extra-Terminal (BET) Inhibitor Using Scaffold-Hopping and Structure-Guided Drug Design.
Gavai, Ashvinikumar V; Norris, Derek; Delucca, George; Tortolani, David; Tokarski, John S; Dodd, Dharmpal; O'Malley, Daniel; Zhao, Yufen; Quesnelle, Claude; Gill, Patrice; Vaccaro, Wayne; Huynh, Tram; Ahuja, Vijay; Han, Wen-Ching; Mussari, Christopher; Harikrishnan, Lalgudi; Kamau, Muthoni; Poss, Michael; Sheriff, Steven; Yan, Chunhong; Marsilio, Frank; Menard, Krista; Wen, Mei-Li; Rampulla, Richard; Wu, Dauh-Rurng; Li, Jianqing; Zhang, Huiping; Li, Peng; Sun, Dawn; Yip, Henry; Traeger, Sarah C; Zhang, Yingru; Mathur, Arvind; Zhang, Haiying; Huang, Christine; Yang, Zheng; Ranasinghe, Asoka; Everlof, Gerry; Raghavan, Nirmala; Tye, Ching Kim; Wee, Susan; Hunt, John T; Vite, Gregory; Westhouse, Richard; Lee, Francis Y.
Afiliação
  • Gavai AV; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Norris D; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Delucca G; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Tortolani D; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Tokarski JS; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Dodd D; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • O'Malley D; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Zhao Y; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Quesnelle C; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Gill P; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Vaccaro W; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Huynh T; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Ahuja V; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Han WC; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Mussari C; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Harikrishnan L; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Kamau M; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Poss M; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Sheriff S; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Yan C; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Marsilio F; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Menard K; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Wen ML; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Rampulla R; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Wu DR; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Li J; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Zhang H; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Li P; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Sun D; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Yip H; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Traeger SC; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Zhang Y; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Mathur A; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Zhang H; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Huang C; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Yang Z; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Ranasinghe A; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Everlof G; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Raghavan N; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Tye CK; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Wee S; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Hunt JT; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Vite G; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Westhouse R; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Lee FY; Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.
J Med Chem ; 64(19): 14247-14265, 2021 10 14.
Article em En | MEDLINE | ID: mdl-34543572
ABSTRACT
Inhibition of the bromodomain and extra-terminal (BET) family of adaptor proteins is an attractive strategy for targeting transcriptional regulation of key oncogenes, such as c-MYC. Starting with the screening hit 1, a combination of structure-activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole 9 with favorable binding to the tryptophan, proline, and phenylalanine (WPF) shelf conserved in the BET family. Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of 18 (BMS-986158) with excellent potency in binding and functional assays. On the basis of its favorable PK profile and robust in vivo activity in a panel of hematologic and solid tumor models, BMS-986158 was selected as a candidate for clinical evaluation.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fenilalanina / Triptofano / Prolina / Carbazóis / Descoberta de Drogas / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fenilalanina / Triptofano / Prolina / Carbazóis / Descoberta de Drogas / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos