title: Structure-based design of N-substituted 1-hydroxy-4-sulfamoyl-2-naphthoates as selective inhibitors of the Mcl-1 oncoprotein.
abstract: Structure-based drug design was utilized to develop novel, 1-hydroxy-2-naphthoate-based small-molecule inhibitors of Mcl-1. Ligand design was driven by exploiting a salt bridge with R263 and interactions with the p2 pocket of the protein. Significantly, target molecules were accessed in just two synthetic steps, suggesting further optimization will require minimal synthetic effort. Molecular modeling using the Site-Identification by Ligand Competitive Saturation (SILCS) approach was used to qualitatively direct ligand design as well as develop quantitative models for inhibitor binding affinity to Mcl-1 and the Bcl-2 relative Bcl-xL as well as for the specificity of binding to the two proteins. Results indicated hydrophobic interactions in the p2 pocket dominated affinity of the most favourable binding ligand (3bl: Ki = 31 nM). Compounds were up to 19-fold selective for Mcl-1 over Bcl-xL. Selectivity of the inhibitors was driven by interactions with the deeper p2 pocket in Mcl-1 versus Bcl-xL. The SILCS-based SAR of the present compounds represents the foundation for the development of Mcl-1 specific inhibitors with the potential to treat a wide range of solid tumours and hematological cancers, including acute myeloid leukemia.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA.
authors.forename: Maryanna E
authors.initials: ME
authors.lastname: Lanning
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA.
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Yap
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Chauhan
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA.
authors.forename: Lijia
authors.initials: L
authors.lastname: Chen
authors.affiliation: School of Chemistry, University of Cardiff, CF10 3AT, UK.
authors.forename: Ellis
authors.initials: E
authors.lastname: Whiting
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 22 S. Greene St., Baltimore, MD 21201, USA.
authors.forename: Lakshmi S
authors.initials: LS
authors.lastname: Pidugu
authors.affiliation: PharmD Program, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Atkinson
authors.affiliation: Bryn Mawr School, 109 W. Melrose Ave., Baltimore, MD 21210, USA.
authors.forename: Hala
authors.initials: H
authors.lastname: Bailey
authors.affiliation: PharmD Program, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA.
authors.forename: Willy
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 22 S. Greene St., Baltimore, MD 21201, USA.
authors.forename: Braden M
authors.initials: BM
authors.lastname: Roth
authors.affiliation: Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Hynicka
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA; University of Maryland Greenebaum Cancer Center, 22 S. Greene St., Baltimore, MD 21201, USA.
authors.forename: Kirsty
authors.initials: K
authors.lastname: Chesko
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 22 S. Greene St., Baltimore, MD 21201, USA; University of Maryland Greenebaum Cancer Center, 22 S. Greene St., Baltimore, MD 21201, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Toth
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA; University of Maryland Greenebaum Cancer Center, 22 S. Greene St., Baltimore, MD 21201, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Shapiro
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA; University of Maryland Greenebaum Cancer Center, 22 S. Greene St., Baltimore, MD 21201, USA.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: MacKerell
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 22 S. Greene St., Baltimore, MD 21201, USA; University of Maryland Greenebaum Cancer Center, 22 S. Greene St., Baltimore, MD 21201, USA.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Wilder
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA; University of Maryland Greenebaum Cancer Center, 22 S. Greene St., Baltimore, MD 21201, USA. Electronic address: sfletcher@rx.umaryland.edu.
authors.forename: Steven
authors.initials: S
authors.lastname: Fletcher
mesh_terms: D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D015394:Molecular Structure; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors*; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000612621:1-hydroxy-4-sulfamoyl-2-naphthoate; D002264:Carboxylic Acids; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009281:Naphthalenes
keywords: Apoptosis; Bcl-x(L); Cancer; Mcl-1; Protein–protein interaction