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Inhibition of RAS-driven signaling and tumorigenesis with a pan-RAS monobody targeting the Switch I/II pocket.
Wallon, Lauren; Khan, Imran; Teng, Kai Wen; Koide, Akiko; Zuberi, Mariyam; Li, Jianping; Ketavarapu, Gayatri; Traaseth, Nathaniel J; O'Bryan, John P; Koide, Shohei.
Afiliação
  • Wallon L; Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016.
  • Khan I; Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425.
  • Teng KW; Ralph H. Johnson VA Medical Center, Charleston, SC 29401.
  • Koide A; Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016.
  • Zuberi M; Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016.
  • Li J; Department of Medicine, New York University School of Medicine, New York, NY 10016.
  • Ketavarapu G; Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425.
  • Traaseth NJ; Ralph H. Johnson VA Medical Center, Charleston, SC 29401.
  • O'Bryan JP; Department of Chemistry, New York University, New York, NY 10003.
  • Koide S; Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016.
Proc Natl Acad Sci U S A ; 119(43): e2204481119, 2022 10 25.
Article em En | MEDLINE | ID: mdl-36252024
RAS mutants are major therapeutic targets in oncology with few efficacious direct inhibitors available. The identification of a shallow pocket near the Switch II region on RAS has led to the development of small-molecule drugs that target this site and inhibit KRAS(G12C) and KRAS(G12D). To discover other regions on RAS that may be targeted for inhibition, we have employed small synthetic binding proteins termed monobodies that have a strong propensity to bind to functional sites on a target protein. Here, we report a pan-RAS monobody, termed JAM20, that bound to all RAS isoforms with nanomolar affinity and demonstrated limited nucleotide-state specificity. Upon intracellular expression, JAM20 potently inhibited signaling mediated by all RAS isoforms and reduced oncogenic RAS-mediated tumorigenesis in vivo. NMR and mutation analysis determined that JAM20 bound to a pocket between Switch I and II, which is similarly targeted by low-affinity, small-molecule inhibitors, such as BI-2852, whose in vivo efficacy has not been demonstrated. Furthermore, JAM20 directly competed with both the RAF(RBD) and BI-2852. These results provide direct validation of targeting the Switch I/II pocket for inhibiting RAS-driven tumorigenesis. More generally, these results demonstrate the utility of tool biologics as probes for discovering and validating druggable sites on challenging targets.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Produtos Biológicos / Proteínas Proto-Oncogênicas p21(ras) Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Produtos Biológicos / Proteínas Proto-Oncogênicas p21(ras) Idioma: En Ano de publicação: 2022 Tipo de documento: Article