Design,synthesis and biological evaluation of FLT3 covalent inhibitors with a resorcylic acid core |
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Affiliation: | 1. Neuro/Immuno Discovery Biology, Biogen, Cambridge, MA, USA;2. Biomarkers and Experimental Medicine, Biogen, Cambridge, MA, USA;1. Neuroinflammation Gene Therapy Laboratory, Institut Pasteur de Montevideo, Montevideo, Uruguay;2. Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República (UDELAR), Montevideo, Uruguay;3. Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain;4. Department de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain;5. CIBER en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Bellaterra, 08193 Barcelona, Spain |
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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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Keywords: | FLT3 Covalent inhibitor Michael acceptor Maleimide Acrylamide Resorcylic acid lactones |
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