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. SIGNIFICANCE STATEMENT: Here, we describe the anticancer 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 taxane-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 β-tubulin that could account for the improved anticancer activity. These findings support continued preclinical development of discodermolide, particularly in the chemorefractory setting.

中文翻译：

---

微管蛋白配体 (+)-Discodermolide 的结构细化以减轻化疗介导的衰老。

天然产物 (+)-discodermolide (DDM) 是一种微管稳定剂和有效的衰老诱导剂。我们改进了 DDM 的结构并评估了新型同源物在三阴性乳腺癌和卵巢癌中的活性，这些恶性肿瘤通常会屈服于紫杉烷抗性。先前的结构-活性分析将内酯和二烯鉴定为具有抗癌活性的部分，从而确定本文所述结构改进研究的优先事项。相对于紫杉醇，具有单二烯和简化内酯的同源物具有更好的抗癌功效，尤其是在耐药模型中。具体而言，这些同类物之一 B2 证明：1) 改善了药理学特性，特别是增加了可实现的最大反应和曲线下面积，并降低了 EC50；2) 与紫杉醇或 DDM 相关的基因异质癌细胞系的统一剂量反应曲线；3) 相对于 DDM 降低衰老诱导的倾向；4) 与紫杉醇或 DDM 相比，在癌细胞中具有更好的长期活性；和 5) 治疗癌细胞中转移特征的减弱。为了对比微管蛋白中 B2 与 DDM 的结合，X 射线晶体学研究揭示了与去除 C2-甲基和 C3-羟基相关的内酯环位置的变化。因此，B2 可能更适应紫杉烷位点相对于 DDM 的变化，这可以解释其有利的特性。总之，我们已经确定了一种具有广泛抗癌功效的 DDM 同源物，它也降低了诱导化疗介导的衰老的风险。重要性声明：在这里，我们描述了微管蛋白聚合分子 (+)-discodermolide 的新型同源物的抗癌活性。确定了一种先导分子，其在紫杉烷敏感和紫杉烷抗性癌细胞模型中表现出改善的剂量反应特征，降低了化疗介导的衰老风险，并抑制了肿瘤细胞侵袭终点。X 射线晶体学研究确定了与 β-微管蛋白结合姿势的细微变化，这可能是抗癌活性提高的原因。这些发现支持 discodermolide 的持续临床前开发，特别是在化学难治性环境中。降低化疗介导的衰老风险，并抑制肿瘤细胞侵袭终点。X 射线晶体学研究确定了与 β-微管蛋白结合姿势的细微变化，这可能是抗癌活性提高的原因。这些发现支持 discodermolide 的持续临床前开发，特别是在化学难治性环境中。降低化疗介导的衰老风险，并抑制肿瘤细胞侵袭终点。X 射线晶体学研究确定了与 β-微管蛋白结合姿势的细微变化，这可能是抗癌活性提高的原因。这些发现支持 discodermolide 的持续临床前开发，特别是在化学难治性环境中。