title: 3-Substituted-N-(4-hydroxynaphthalen-1-yl)arylsulfonamides as a novel class of selective Mcl-1 inhibitors: structure-based design, synthesis, SAR, and biological evaluation.
abstract: Mcl-1, an antiapoptotic member of the Bcl-2 family of proteins, is a validated and attractive target for cancer therapy. Overexpression of Mcl-1 in many cancers results in disease progression and resistance to current chemotherapeutics. Utilizing high-throughput screening, compound 1 was identified as a selective Mcl-1 inhibitor and its binding to the BH3 binding groove of Mcl-1 was confirmed by several different, but complementary, biochemical and biophysical assays. Guided by structure-based drug design and supported by NMR experiments, comprehensive SAR studies were undertaken and a potent and selective inhibitor, compound 21, was designed which binds to Mcl-1 with a Ki of 180 nM. Biological characterization of 21 showed that it disrupts the interaction of endogenous Mcl-1 and biotinylated Noxa-BH3 peptide, causes cell death through a Bak/Bax-dependent mechanism, and selectively sensitizes Eμ-myc lymphomas overexpressing Mcl-1, but not Eμ-myc lymphoma cells overexpressing Bcl-2. Treatment of human leukemic cell lines with compound 21 resulted in cell death through activation of caspase-3 and induction of apoptosis.
authors.affiliation: Department of Pathology, University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
authors.forename: Fardokht A
authors.initials: FA
authors.lastname: Abulwerdi
authors.forename: Chenzhong
authors.initials: C
authors.lastname: Liao
authors.forename: Ahmed S
authors.initials: AS
authors.lastname: Mady
authors.forename: Jordan
authors.initials: J
authors.lastname: Gavin
authors.forename: Chenxi
authors.initials: C
authors.lastname: Shen
authors.forename: Tomasz
authors.initials: T
authors.lastname: Cierpicki
authors.forename: Jeanne A
authors.initials: JA
authors.lastname: Stuckey
authors.forename: H D Hollis
authors.initials: HD
authors.lastname: Showalter
authors.forename: Zaneta
authors.initials: Z
authors.lastname: Nikolovska-Coleska
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
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