title: A competitive stapled peptide screen identifies a selective small molecule that overcomes MCL-1-dependent leukemia cell survival.
abstract: Cancer cells hijack BCL-2 family survival proteins to suppress the death effectors and thereby enforce an immortal state. This is accomplished biochemically by an antiapoptotic surface groove that neutralizes the proapoptotic BH3 α helix of death proteins. Antiapoptotic MCL-1 in particular has emerged as a ubiquitous resistance factor in cancer. Although targeting the BCL-2 antiapoptotic subclass effectively restores the death pathway in BCL-2-dependent cancer, the development of molecules tailored to the binding specificity of MCL-1 has lagged. We previously discovered that a hydrocarbon-stapled MCL-1 BH3 helix is an exquisitely selective MCL-1 antagonist. By deploying this unique reagent in a competitive screen, we identified an MCL-1 inhibitor molecule that selectively targets the BH3-binding groove of MCL-1, neutralizes its biochemical lock-hold on apoptosis, and induces caspase activation and leukemia cell death in the specific context of MCL-1 dependence.
authors.affiliation: Departments of Pediatric Oncology and the Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Division of Hematology/Oncology, Children's Hospital Boston, and Department of Pediatrics, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Cohen
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Stewart
authors.forename: Evripidis
authors.initials: E
authors.lastname: Gavathiotis
authors.forename: Jared L
authors.initials: JL
authors.lastname: Tepper
authors.forename: Susanne R
authors.initials: SR
authors.lastname: Bruekner
authors.forename: Brian
authors.initials: B
authors.lastname: Koss
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Opferman
authors.forename: Loren D
authors.initials: LD
authors.lastname: Walensky
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010455:Peptides; D054852:Small Molecule Libraries