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Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription.
Struntz, Nicholas B; Chen, Andrew; Deutzmann, Anja; Wilson, Robert M; Stefan, Eric; Evans, Helen L; Ramirez, Maricela A; Liang, Tong; Caballero, Francisco; Wildschut, Mattheus H E; Neel, Dylan V; Freeman, David B; Pop, Marius S; McConkey, Marie; Muller, Sandrine; Curtin, Brice H; Tseng, Hanna; Frombach, Kristen R; Butty, Vincent L; Levine, Stuart S; Feau, Clementine; Elmiligy, Sarah; Hong, Jiyoung A; Lewis, Timothy A; Vetere, Amedeo; Clemons, Paul A; Malstrom, Scott E; Ebert, Benjamin L; Lin, Charles Y; Felsher, Dean W; Koehler, Angela N.
Afiliação
  • Struntz NB; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Techno
  • Chen A; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Techno
  • Deutzmann A; Division of Oncology, Departments of Medicine and Pathology Stanford School of Medicine, Stanford, CA 94305, USA.
  • Wilson RM; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Techno
  • Stefan E; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Evans HL; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Techno
  • Ramirez MA; Department of Molecular and Human Genetics and Verna & Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
  • Liang T; Department of Molecular and Human Genetics and Verna & Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
  • Caballero F; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Wildschut MHE; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Neel DV; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Freeman DB; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Kronos Bio, Inc., Cambridge, MA 02139, USA.
  • Pop MS; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Kronos Bio, Inc., Cambridge, MA 02139, USA.
  • McConkey M; Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Muller S; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Curtin BH; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Techno
  • Tseng H; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Frombach KR; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Butty VL; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; BioMicro Center, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • Levine SS; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; BioMicro Center, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • Feau C; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Elmiligy S; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • Hong JA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Bost
  • Lewis TA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Vetere A; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Clemons PA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Malstrom SE; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • Ebert BL; Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Lin CY; Department of Molecular and Human Genetics and Verna & Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Therapeutic Innovation Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • Felsher DW; Division of Oncology, Departments of Medicine and Pathology Stanford School of Medicine, Stanford, CA 94305, USA.
  • Koehler AN; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Techno
Cell Chem Biol ; 26(5): 711-723.e14, 2019 05 16.
Article em En | MEDLINE | ID: mdl-30880155
ABSTRACT
The transcription factor Max is a basic-helix-loop-helix leucine zipper (bHLHLZ) protein that forms homodimers or interacts with other bHLHLZ proteins, including Myc and Mxd proteins. Among this dynamic network of interactions, the Myc/Max heterodimer has crucial roles in regulating normal cellular processes, but its transcriptional activity is deregulated in a majority of human cancers. Despite this significance, the arsenal of high-quality chemical probes to interrogate these proteins remains limited. We used small molecule microarrays to identify compounds that bind Max in a mechanistically unbiased manner. We discovered the asymmetric polycyclic lactam, KI-MS2-008, which stabilizes the Max homodimer while reducing Myc protein and Myc-regulated transcript levels. KI-MS2-008 also decreases viable cancer cell growth in a Myc-dependent manner and suppresses tumor growth in vivo. This approach demonstrates the feasibility of modulating Max with small molecules and supports altering Max dimerization as an alternative approach to targeting Myc.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Compostos Policíclicos / Proteínas Repressoras / Transcrição Gênica / Proteínas Proto-Oncogênicas c-myc / Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos / Bibliotecas de Moléculas Pequenas / Lactamas Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Revista: Cell Chem Biol Ano de publicação: 2019 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Compostos Policíclicos / Proteínas Repressoras / Transcrição Gênica / Proteínas Proto-Oncogênicas c-myc / Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos / Bibliotecas de Moléculas Pequenas / Lactamas Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Revista: Cell Chem Biol Ano de publicação: 2019 Tipo de documento: Article