title: Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods.
abstract: Myeloid cell leukemia-1 (Mcl-1) is a member of the Bcl-2 family of proteins responsible for the regulation of programmed cell death. Amplification of Mcl-1 is a common genetic aberration in human cancer whose overexpression contributes to the evasion of apoptosis and is one of the major resistance mechanisms for many chemotherapies. Mcl-1 mediates its effects primarily through interactions with pro-apoptotic BH3 containing proteins that achieve high affinity for the target by utilizing four hydrophobic pockets in its binding groove. Here we describe the discovery of Mcl-1 inhibitors using fragment-based methods and structure-based design. These novel inhibitors exhibit low nanomolar binding affinities to Mcl-1 and >500-fold selectivity over Bcl-xL. X-ray structures of lead Mcl-1 inhibitors when complexed to Mcl-1 provided detailed information on how these small-molecules bind to the target and were used extensively to guide compound optimization.
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Pelz
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Bian
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States.
authors.forename: Subrata
authors.initials: S
authors.lastname: Shaw
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States.
authors.forename: James C
authors.initials: JC
authors.lastname: Tarr
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States.
authors.forename: Johannes
authors.initials: J
authors.lastname: Belmar
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States.
authors.forename: Claire
authors.initials: C
authors.lastname: Gregg
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States.
authors.forename: DeMarco V
authors.initials: DV
authors.lastname: Camper
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Goodwin
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States.
authors.forename: Allison L
authors.initials: AL
authors.lastname: Arnold
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States.
authors.forename: John L
authors.initials: JL
authors.lastname: Sensintaffar
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States.
authors.forename: Anders
authors.initials: A
authors.lastname: Friberg
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States.
authors.forename: Olivia W
authors.initials: OW
authors.lastname: Rossanese
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States.
authors.forename: Taekyu
authors.initials: T
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Olejniczak
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Fesik
mesh_terms: D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D007211:Indoles; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D013449:Sulfonamides