Structural refinement of the tubulin ligand (+)-Discodermolide to attenuate chemotherapy-mediated senescence

Boying Guo, Alicia Rodriguez-Gabin, Andrea E. Prota, Tobias Mühlethaler, Nan Zhang, Kenny Ye, Michel O. Steinmetz, Susan Band Horwitz, Amos B. Smith, Hayley M. McDaid

Research output: Contribution to journalArticle

Abstract

The natural product (+)-discodermolide (DDM) is a microtubule stabilizing agent and potent inducer of senescence. We refined the structure of DDM and evaluated the activity of novel congeners in triple negative breast and ovarian cancers, malignancies that typically succumb to taxane resistance. Previous structure-activity analyses identified the lactone and diene as moieties conferring anticancer activity, thus identifying priorities for the structural refinement studies described herein. Congeners possessing the monodiene with a simplified lactone had superior anticancer efficacy relative to taxol, particularly in resistant models. Specifically, one of these congeners, B2, demonstrated 1) improved pharmacologic properties, specifically increased maximum response achievable and area under the curve, and decreased EC50; 2) a uniform dose-response profile across genetically heterogeneous cancer cell lines relative to taxol or DDM; 3) reduced propensity for senescence induction relative to DDM; 4) superior long-term activity in cancer cells versus taxol or DDM; and 5) attenuation of metastatic characteristics in treated cancer cells. To contrast the binding of B2 versus DDM in tubulin, X-ray crystallography studies revealed a shift in the position of the lactone ring associated with removal of the C2-methyl and C3-hydroxyl. Thus, B2 may be more adaptable to changes in the taxane site relative to DDM that could account for its favorable properties. In conclusion, we have identified a DDM congener with broad range anticancer efficacy that also has decreased risk of inducing chemotherapy-mediated senescence.

Original languageEnglish (US)
Pages (from-to)156-167
Number of pages12
JournalMolecular Pharmacology
Volume98
Issue number2
DOIs
StatePublished - 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Guo, B., Rodriguez-Gabin, A., Prota, A. E., Mühlethaler, T., Zhang, N., Ye, K., Steinmetz, M. O., Horwitz, S. B., Smith, A. B., & McDaid, H. M. (2020). Structural refinement of the tubulin ligand (+)-Discodermolide to attenuate chemotherapy-mediated senescence. Molecular Pharmacology, 98(2), 156-167. https://doi.org/10.1124/MOL.119.117457