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Multivalent Small-Molecule Pan-RAS Inhibitors.
Welsch, Matthew E; Kaplan, Anna; Chambers, Jennifer M; Stokes, Michael E; Bos, Pieter H; Zask, Arie; Zhang, Yan; Sanchez-Martin, Marta; Badgley, Michael A; Huang, Christine S; Tran, Timothy H; Akkiraju, Hemanth; Brown, Lewis M; Nandakumar, Renu; Cremers, Serge; Yang, Wan Seok; Tong, Liang; Olive, Kenneth P; Ferrando, Adolfo; Stockwell, Brent R.
Afiliação
  • Welsch ME; Department of Chemistry, Columbia University, New York, NY 10027, USA.
  • Kaplan A; Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
  • Chambers JM; Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
  • Stokes ME; Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
  • Bos PH; Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
  • Zask A; Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
  • Zhang Y; Department of Chemistry, Columbia University, New York, NY 10027, USA.
  • Sanchez-Martin M; Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA.
  • Badgley MA; Department of Pathology, Columbia University Medical Center, New York, NY 10032, USA; Division of Digestive and Liver Diseases in the Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
  • Huang CS; Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
  • Tran TH; Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
  • Akkiraju H; Department of Biological Sciences, Columbia University, New York, NY 10027, USA; Quantitative Proteomics and Metabolomics Center, Columbia University, New York, NY 10027, USA.
  • Brown LM; Department of Biological Sciences, Columbia University, New York, NY 10027, USA; Quantitative Proteomics and Metabolomics Center, Columbia University, New York, NY 10027, USA.
  • Nandakumar R; Irving Institute for Clinical and Translational Research, Columbia University Medical Center, New York, NY 10032, USA.
  • Cremers S; Department of Pathology, Columbia University Medical Center, New York, NY 10032, USA; Irving Institute for Clinical and Translational Research, Columbia University Medical Center, New York, NY 10032, USA.
  • Yang WS; Department of Biological Sciences, St. John's University, Queens, NY 11439, USA.
  • Tong L; Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
  • Olive KP; Department of Pathology, Columbia University Medical Center, New York, NY 10032, USA; Division of Digestive and Liver Diseases in the Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
  • Ferrando A; Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology, Columbia University Medical Center, New York, NY 10032, USA; Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
  • Stockwell BR; Department of Chemistry, Columbia University, New York, NY 10027, USA; Department of Biological Sciences, Columbia University, New York, NY 10027, USA. Electronic address: bstockwell@columbia.edu.
Cell ; 168(5): 878-889.e29, 2017 02 23.
Article em En | MEDLINE | ID: mdl-28235199
Design of small molecules that disrupt protein-protein interactions, including the interaction of RAS proteins and their effectors, may provide chemical probes and therapeutic agents. We describe here the synthesis and testing of potential small-molecule pan-RAS ligands, which were designed to interact with adjacent sites on the surface of oncogenic KRAS. One compound, termed 3144, was found to bind to RAS proteins using microscale thermophoresis, nuclear magnetic resonance spectroscopy, and isothermal titration calorimetry and to exhibit lethality in cells partially dependent on expression of RAS proteins. This compound was metabolically stable in liver microsomes and displayed anti-tumor activity in xenograft mouse cancer models. These findings suggest that pan-RAS inhibition may be an effective therapeutic strategy for some cancers and that structure-based design of small molecules targeting multiple adjacent sites to create multivalent inhibitors may be effective for some proteins.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Proto-Oncogênicas p21(ras) / Terapia de Alvo Molecular / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Cell Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Proto-Oncogênicas p21(ras) / Terapia de Alvo Molecular / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Cell Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Estados Unidos