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

Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

“…Simpler, non-macrocyclic RAL analogs 275-277 were prepared with acrylamide or maleimide Michael acceptors and inhibited FLT3, albeit with lower potency than the natural products. 108 These compounds were also shown to form adducts with cysteamine by 1 H NMR. The effects of substituents on the ester or aromatic ring were also examined, with the morpholine and isopropyl ester shown in 275-277 generally giving the most potent RAL analogs.…”

The Application of Dioxygenase‐Based Chemoenzymatic Processes to the Total Synthesis of Natural Products

“…By similar means we have also completed total syntheses of both the resorcylica cid lactone L-783.277 (90)a nd its isomer L-783.290 (91), [63] the latter having also been prepared in am ulti-step synthesis from d-ribose [64] and simplified analogues of the former having been evaluated as kinase inhibitors. [65] (v) Cyclopropane-Mediated Ring-expansion Reactions of cis-…”

“…Using related “cutting and stitching” processes we have been able construct a polyoxygenated cyclo‐octane related to the Eastern hemisphere of the structurally remarkable tripartilactam ( 89 ) (Figure ), a target that continues to attract attention but has yet to succumb to total synthesis. By similar means we have also completed total syntheses of both the resorcylic acid lactone L‐783.277 ( 90 ) and its isomer L‐783.290 ( 91 ), the latter having also been prepared in a multi‐step synthesis from d ‐ribose and simplified analogues of the former having been evaluated as kinase inhibitors …”

Discover Novel Covalent Inhibitors Targeting FLT3 through Hybrid Virtual Screening Strategy

“…[16][17][18] To overcome the problem of drug resistance caused by mutations, covalent inhibitors may be a good solution due to their excellent selectivity and strong affinity. 19,20) FF-10101, an FLT3 covalent inhibitor, showed sustained FLT3 inhibition in patients with refractory or relapsed AML in phase I clinical study, including those who are resistant to Gilteritinib. 21) In this study, we found that the ATP binding pocket of FLT3 has two covalent binding sites: Cys 695 and Cys 828 (Fig.…”