Structure-activity relationships of tubulysin analogues.

Autor: Courter JR; Seattle Genetics, Inc., 21823 30(th) Drive SE, Bothell, WA 98021, USA. Electronic address: JCourter@seagen.com., Hamilton JZ; Seattle Genetics, Inc., 21823 30(th) Drive SE, Bothell, WA 98021, USA., Hendrick NR; Seattle Genetics, Inc., 21823 30(th) Drive SE, Bothell, WA 98021, USA., Zaval M; Seattle Genetics, Inc., 21823 30(th) Drive SE, Bothell, WA 98021, USA., Waight AB; Seattle Genetics, Inc., 21823 30(th) Drive SE, Bothell, WA 98021, USA., Lyon RP; Seattle Genetics, Inc., 21823 30(th) Drive SE, Bothell, WA 98021, USA., Senter PD; Seattle Genetics, Inc., 21823 30(th) Drive SE, Bothell, WA 98021, USA., Jeffrey SC; Seattle Genetics, Inc., 21823 30(th) Drive SE, Bothell, WA 98021, USA., Burke PJ; Seattle Genetics, Inc., 21823 30(th) Drive SE, Bothell, WA 98021, USA. Electronic address: PBurke@seagen.com.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2020 Jul 15; Vol. 30 (14), pp. 127241. Date of Electronic Publication: 2020 May 05.
DOI: 10.1016/j.bmcl.2020.127241
Abstrakt: 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.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: J.R.C., J.Z.H., N.R.H., M.Z., R.P.L, P.D.S., S.C.J. and P.J.B. are current employees of Seattle Genetics. A.B.W. is a former employee of Seattle Genetics.
(Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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