2. Academic Validation
  3. Structure-activity relationships of tubulysin analogues

Structure-activity relationships of tubulysin analogues

  • Bioorg Med Chem Lett. 2020 Jul 15;30(14):127241. doi: 10.1016/j.bmcl.2020.127241.
Joel R Courter 1,  Joseph Z Hamilton 2,  Nathaniel R Hendrick 2,  Margo Zaval 2,  Andrew B Waight 2,  Robert P Lyon 2,  Peter D Senter 2,  Scott C Jeffrey 2,  Patrick J Burke 3
Affiliations

Affiliations

  • 1 Seattle Genetics, Inc., 21823 30(th) Drive SE, Bothell, WA 98021, USA. Electronic address: JCourter@seagen.com.
  • 2 Seattle Genetics, Inc., 21823 30(th) Drive SE, Bothell, WA 98021, USA.
  • 3 Seattle Genetics, Inc., 21823 30(th) Drive SE, Bothell, WA 98021, USA. Electronic address: PBurke@seagen.com.
PMID: 32527543 DOI: 10.1016/j.bmcl.2020.127241
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.

Keywords

Antibody-drug conjugates; Microtubule-disrupting agents; Multi-drug resistant; Structure-activity relationships; Tubulin binders; Tubulysin.

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