title: Discovery and biological characterization of potent myeloid cell leukemia-1 inhibitors.
abstract: Myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of proteins that when overexpressed is associated with high tumor grade, poor survival, and resistance to chemotherapy. Mcl-1 is amplified in many human cancers, and knockdown of Mcl-1 using RNAi can lead to apoptosis. Thus, Mcl-1 is a promising cancer target. Here, we describe the discovery of picomolar Mcl-1 inhibitors that cause caspase activation, mitochondrial depolarization, and selective growth inhibition. These compounds represent valuable tools to study the role of Mcl-1 in cancer and serve as useful starting points for the discovery of clinically useful Mcl-1 inhibitors.
  Comp. 2: 5IEZ; Comp. 5: 5IF4.
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Taekyu
authors.initials: T
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Bian
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Leah J
authors.initials: LJ
authors.lastname: Hogdal
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Sensintaffar
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Goodwin
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Johannes
authors.initials: J
authors.lastname: Belmar
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Subrata
authors.initials: S
authors.lastname: Shaw
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Tarr
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Nagarathanam
authors.initials: N
authors.lastname: Veerasamy
authors.affiliation: Department of Hematology and Medical Oncology and The Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Matulis
authors.affiliation: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Koss
authors.affiliation: Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Fischer
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Allison L
authors.initials: AL
authors.lastname: Arnold
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: DeMarco V
authors.initials: DV
authors.lastname: Camper
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Carrie F
authors.initials: CF
authors.lastname: Browning
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Olivia W
authors.initials: OW
authors.lastname: Rossanese
authors.affiliation: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Budhraja
authors.affiliation: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Opferman
authors.affiliation: Department of Hematology and Medical Oncology and The Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Boise
authors.affiliation: Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Savona
authors.affiliation: Department of Adult Oncology, The Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Letai
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Olejniczak
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Fesik
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D000072224:Bcl-2-Like Protein 11 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D055808:Drug Discovery; D006801:Humans; D047468:Immunoprecipitation; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000072224:Bcl-2-Like Protein 11; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D051020:bcl-X Protein
keywords: apoptosis; cancer; drug discovery; myeloid cell leukemia 1; structure-based drug design