2. Academic Validation
  3. Design, synthesis and biological evaluation of FLT3 covalent inhibitors with a resorcylic acid core

Design, synthesis and biological evaluation of FLT3 covalent inhibitors with a resorcylic acid core

  • Bioorg Med Chem. 2014 Dec 1;22(23):6625-6637. doi: 10.1016/j.bmc.2014.10.006.
Jin Xu 1,  Esther H Q Ong 2,  Jeffrey Hill 2,  Anqi Chen 3,  Christina L L Chai 4
Affiliations

Affiliations

  • 1 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.
  • 2 Protein Biochemistry Enzymology, Experimental Therapeutic Centre (ETC), A*STAR, 31 Biopolis Way, Nanos Level 3, 138669, Singapore.
  • 3 Organic Chemistry, Institute of Chemical and Engineering Sciences (ICES), A*STAR, 8 Biomedical Grove, Neuros #07-01, 138665, Singapore. Electronic address: [email protected].
  • 4 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: [email protected].
PMID: 25456387 DOI: 10.1016/j.bmc.2014.10.006
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).

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