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ID: ALA4725251
Journal: Bioorg Med Chem Lett
Title: Structure-activity relationships of tubulysin analogues.
Authors: Courter JR,Hamilton JZ,Hendrick NR,Zaval M,Waight AB,Lyon RP,Senter PD,Jeffrey SC,Burke PJ
Abstract: The tubulysins are an emerging antibody-drug conjugate (ADC) payload that maintain potent anti-proliferative activity against cells that exhibit the multi-drug resistant (MDR) phenotype. These drugs possess a C-11 acetate known to be hydrolytically unstable in plasma, and loss of the acetate significantly attenuates cytotoxicity. Structure-activity relationship studies were undertaken to identify stable C-11 tubulysin analogues that maintain affinity for tubulin and potent cytotoxicity. After identifying several C-11 alkoxy analogues that possess comparable biological activity to tubulysin M with significantly improved plasma stability, additional analogues of both the Ile residue and N-terminal position were synthesized. These studies revealed that minor changes within the tubulin binding site of tubulysin can profoundly alter the activity of this chemotype, particularly against MDR-positive cell types.
CiteXplore: 32527543