6ses

Publication Abstract from PubMed

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 anti-cancer activity; thus identifying priorities for the structural refinement studies described herein. Congeners possessing the monodiene with a simplified lactone had superior anti-cancer efficacy relative to Taxol, particularly in resistant models. Specifically, one of these congeners, B2, demonstrated (i) improved pharmacologic properties, specifically, increased EMax and AUC, and decreased EC50; (ii) a uniform dose-response profile across genetically heterogeneous cancer cell lines relative to Taxol or DDM; (iii) reduced propensity for senescence induction relative to DDM; (iv) superior long-term activity in cancer cells versus Taxol or DDM, and (v) 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 high-efficiency DDM congener with broad range anti-cancer efficacy that also has decreased risk of inducing chemotherapy-mediated senescence. SIGNIFICANCE STATEMENT: Here, we describe the anti-cancer activity of novel congeners of the tubulin-polymerizing molecule (+)-discodermolide. A lead molecule is identified that exhibits an improved dose-response profile in taxane-sensitive and -resistant cancer cell models, diminished risk of chemotherapy-mediated senescence and suppression of tumor cell invasion endpoints. X-ray crystallography studies identify subtle changes in the pose of binding to beta-tubulin that could account for the improved anti-cancer activity. These findings support continued pre-clinical development of discodermolide, particularly in the chemorefractory setting.

Structural Refinement of the Tubulin Ligand (+)-Discodermolide to Attenuate Chemotherapy-Mediated Senescence.,Guo B, Rodriguez-Gabin A, Prota A, Muhlethaler T, Zhang N, Ye K, Steinmetz MO, Horwitz SB, Smith AB 3rd, McDaid H Mol Pharmacol. 2020 Jun 26. pii: mol.119.117457. doi: 10.1124/mol.119.117457. PMID:32591477^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.