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Discovery of potent and efficacious cyanoguanidine-containing nicotinamide phosphoribosyltransferase (Nampt) inhibitors.
Zheng, Xiaozhang; Baumeister, Timm; Buckmelter, Alexandre J; Caligiuri, Maureen; Clodfelter, Karl H; Han, Bingsong; Ho, Yen-Ching; Kley, Nikolai; Lin, Jian; Reynolds, Dominic J; Sharma, Geeta; Smith, Chase C; Wang, Zhongguo; Dragovich, Peter S; Oh, Angela; Wang, Weiru; Zak, Mark; Wang, Yunli; Yuen, Po-Wai; Bair, Kenneth W.
Afiliação
  • Zheng X; Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA. Electronic address: xzheng@formatherapeutics.com.
  • Baumeister T; Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
  • Buckmelter AJ; Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
  • Caligiuri M; Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
  • Clodfelter KH; Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
  • Han B; Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
  • Ho YC; Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
  • Kley N; Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
  • Lin J; Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
  • Reynolds DJ; Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
  • Sharma G; Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
  • Smith CC; Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
  • Wang Z; Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
  • Dragovich PS; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Oh A; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Wang W; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Zak M; Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • Wang Y; Pharmaron Beijing, Co. Ltd, 6 Tai He Road, BDA, Beijing 100176, PR China.
  • Yuen PW; Pharmaron Beijing, Co. Ltd, 6 Tai He Road, BDA, Beijing 100176, PR China.
  • Bair KW; Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
Bioorg Med Chem Lett ; 24(1): 337-43, 2014 Jan 01.
Article em En | MEDLINE | ID: mdl-24279990
ABSTRACT
A co-crystal structure of amide-containing compound (4) in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein and molecular modeling were utilized to design and discover a potent novel cyanoguanidine-containing inhibitor bearing a sulfone moiety (5, Nampt Biochemical IC50=2.5nM, A2780 cell proliferation IC50=9.7nM). Further SAR exploration identified several additional cyanoguanidine-containing compounds with high potency and good microsomal stability. Among these, compound 15 was selected for in vivo profiling and demonstrated good oral exposure in mice. It also exhibited excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model. The co-crystal structure of this compound in complex with the NAMPT protein was also determined.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Ovarianas / Citocinas / Inibidores Enzimáticos / Nicotinamida Fosforribosiltransferase / Descoberta de Drogas / Guanidinas / Neoplasias Experimentais / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Bioorg Med Chem Lett Ano de publicação: 2014 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Ovarianas / Citocinas / Inibidores Enzimáticos / Nicotinamida Fosforribosiltransferase / Descoberta de Drogas / Guanidinas / Neoplasias Experimentais / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Bioorg Med Chem Lett Ano de publicação: 2014 Tipo de documento: Article