title: Allosteric inhibition of antiapoptotic MCL-1.
abstract: MCL-1 is an antiapoptotic BCL-2 family protein that has emerged as a major pathogenic factor in human cancer. Like BCL-2, MCL-1 bears a surface groove whose function is to sequester the BH3 killer domains of proapoptotic BCL-2 family members, a mechanism harnessed by cancer cells to establish formidable apoptotic blockades. Although drugging the BH3-binding groove has been achieved for BCL-2, translating this approach to MCL-1 has been challenging. Here, we report an alternative mechanism for MCL-1 inhibition by small-molecule covalent modification of C286 at a new interaction site distant from the BH3-binding groove. Our structure-function analyses revealed that the BH3 binding capacity of MCL-1 and its suppression of BAX are impaired by molecular engagement, a phenomenon recapitulated by C286W mutagenic mimicry in vitro and in mouse cells. Thus, we characterize an allosteric mechanism for disrupting the antiapoptotic BH3 binding activity of MCL-1, informing a new strategy for disarming MCL-1 in cancer.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Wales
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Escudero
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Cohen
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: James
authors.initials: J
authors.lastname: Luccarelli
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Catherine G
authors.initials: CG
authors.lastname: Gallagher
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Cohen
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Annissa J
authors.initials: AJ
authors.lastname: Huhn
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Bird
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Engen
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Loren D
authors.initials: LD
authors.lastname: Walensky
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D051379:Mice; D056004:Molecular Dynamics Simulation; D016296:Mutagenesis; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects; D000072417:Protein Domains; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000737:chemistry / Q000378:metabolism
chemical_list: C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D054852:Small Molecule Libraries; D051028:bcl-2-Associated X Protein