title: Design, synthesis and biological evaluation of FLT3 covalent  inhibitors with a resorcylic acid core.
abstract: A series of simplified ring-opened resorcylic acid lactone (RAL) derivatives were conveniently synthesized to target FLT3 and its mutants either irreversibly or reversibly. Our design of covalent FLT3 inhibitors is based on cis-enone RALs (e.g., L-783,277) that have a β-resorcylic acid as the core structure. The designed compounds contain three types of Michael acceptors (acrylamide, vinylsulfonamide and maleimide) as potential covalent traps of a cysteine residue at the binding site of kinases. A variety of functional substitutions were also introduced to maximize the binding interactions. Biological evaluations revealed that compound 17, despite the presence of a highly reactive maleimide Michael acceptor, is a potent covalent FLT3 inhibitor which shows some specificity in cellular assays. On the other hand, compounds 2 and 6 containing acrylamide or vinylsulfonamide groups are reversible towards FLT3 binding, and are potent and selective inhibitors of mutant FLT3-ITD versus wt-FLT3. They also inhibit cell proliferation in FLT3-ITD expressing cell line MV-4-11 as compared to wt-FLT3 expressing cell line THP-1 and non-FLT3 cell lines (K562, HL60 and Hek-293T).
authors.affiliation: Organic Chemistry, Institute of Chemical and Engineering Sciences (ICES), A*STAR, 8 Biomedical Grove, Neuros #07-01, 138665, Singapore; Department of Pharmacy, National University of Singapore, 18 Science Drive 4, 117543, Singapore.
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Protein Biochemistry Enzymology, Experimental Therapeutic Centre (ETC), A*STAR, 31 Biopolis Way, Nanos Level 3, 138669, Singapore.
authors.forename: Esther H Q
authors.initials: EHQ
authors.lastname: Ong
authors.affiliation: Protein Biochemistry Enzymology, Experimental Therapeutic Centre (ETC), A*STAR, 31 Biopolis Way, Nanos Level 3, 138669, Singapore.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hill
authors.affiliation: Organic Chemistry, Institute of Chemical and Engineering Sciences (ICES), A*STAR, 8 Biomedical Grove, Neuros #07-01, 138665, Singapore. Electronic address: chen_anqi@ices.a-star.edu.sg.
authors.forename: Anqi
authors.initials: A
authors.lastname: Chen
authors.affiliation: Organic Chemistry, Institute of Chemical and Engineering Sciences (ICES), A*STAR, 8 Biomedical Grove, Neuros #07-01, 138665, Singapore; Department of Pharmacy, National University of Singapore, 18 Science Drive 4, 117543, Singapore. Electronic address: phacllc@nus.edu.sg.
authors.forename: Christina L L
authors.initials: CLL
authors.lastname: Chai
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D057809:HEK293 Cells; D018922:HL-60 Cells; D006801:Humans; D062385:Hydroxybenzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020014:K562 Cells; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012118:Resorcinols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D062385:Hydroxybenzoates; D047428:Protein Kinase Inhibitors; D012118:Resorcinols; C076950:alpha-resorcylic acid; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3