title: Discovery of tricyclic indoles that potently inhibit Mcl-1 using fragment-based methods and structure-based design.
abstract: Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of proteins that is overexpressed and amplified in many cancers. Overexpression of Mcl-1 allows cancer cells to evade apoptosis and contributes to the resistance of cancer cells to be effectively treated with various chemotherapies. From an NMR-based screen of a large fragment library, several distinct chemical scaffolds that bind to Mcl-1 were discovered. Here, we describe the discovery of potent tricyclic 2-indole carboxylic acid inhibitors that exhibit single digit nanomolar binding affinity to Mcl-1 and greater than 1700-fold selectivity over Bcl-xL and greater than 100-fold selectivity over Bcl-2. X-ray structures of these compounds when complexed to Mcl-1 provide detailed information on how these small-molecules bind to the target, which was used 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: Jason P
authors.initials: JP
authors.lastname: Burke
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: 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: 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: 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: 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: Carrie F
authors.initials: CF
authors.lastname: Browning
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States.
authors.forename: Dominico
authors.initials: D
authors.lastname: Vigil
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: 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: 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; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020014:K562 Cells; D008958:Models, Molecular; D008968:Molecular Conformation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D013329:Structure-Activity Relationship; D051020:bcl-X Protein / Q000737:chemistry / Q000378:metabolism
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D007211:Indoles; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D051020:bcl-X Protein
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