Structure-Activity Relationship Studies in Substituted Oxadiazoles as Inducers of Extracellular Vesicles

  • J Med Chem. 2026 Mar 26;69(6):6490-6507. doi: 10.1021/acs.jmedchem.5c02396.
Nikunj M Shukla  1 ,  Tyler D Brown  2 ,  Michael Chan  2 ,  Renna Cozza  2 ,  Shiyin Yao  2 ,  Paola Anguiano Quiroz  2 ,  Tomoko Hayashi  1 ,  Howard B Cottam  1 ,  Maripat Corr  1 ,  Dennis A Carson  1
Affiliations
  • 1. Department of Medicine, University of California San Diego, 9500 Gilam Dr., La Jolla, California 92093, United States.
  • 2. UC San Diego Moores Cancer Center, University of California San Diego, 9500 Gilam Dr., La Jolla, California 92093, United States.
PMID: 41821170 DOI: 10.1021/acs.jmedchem.5c02396
Abstract

We characterized small-molecule compounds discovered through a prior high-throughput screening campaign that enhanced the release of immunostimulatory extracellular vesicles (EVs) and identified compound #645 (compound 1) as an immunomodulatory compound. Here, we performed systematic structure-activity relationship (SAR) studies to probe the scaffold for analogs inducing tetraspanin (CD63) reporter activity, a marker of EV biogenesis and release, in human THP-1 cells. A potent analog 39 was identified, which also stimulated the expression of an immunostimulatory cytokine and costimulatory molecules by antigen-presenting cells and promoted antigen cross-presentation to CD8+ T cells. As its mechanism of action, compound 39 was found to interfere with tubulin polymerization, possibly binding to the nocodazole binding site on beta-tubulin as evident by molecular docking studies. Additionally, 39 preferentially impaired the viability in proliferating cells and may be a potential therapeutic agent for Cancer and immunotherapy applications.

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