Current advancements in tubulin targeting agents for breast cancer: Design strategies, structure-activity relationships, and pharmacological insights.

Breast cancer remains one of the most common causes of cancer mortality worldwide and, despite improvements in early detection and targeted therapies, resistance, recurrence, and metastasis still impair therapeutic success. Microtubule-targeting agents (MTAs) constitute a central pillar of breast cancer therapy by interfering with tubulin homeostasis, arresting mitosis and ultimately leading to apoptosis. Clinically utilized MTAs, such as vinca alkaloids, colchicine-site binders, taxanes, and epothilones, have greatly benefited many patients, for whom taxanes remain the mainstay of chemotherapy. But dose-limiting toxicities, drug pharmacokinetic (PK) liabilities, and resistance impede their effectiveness. New generation structural scaffolds and molecular hybrids have been developed recently with the focus on improving selectivity for binding, overturning mechanisms of resistance, and minimizing systemic toxicity. Members of these compounds that have been tested for efficacy in preclinical studies include tubulin-targeting, dual tubulin-targeting, and multi-targeting tubulin ligands. In this review, we have discussed the design strategies, structure-activity relationships, and pharmacological outcomes for targeting breast cancer via targeting tubulin. This review will act as a baseline for the various research groups currently focused on the development of tubulin-targeting ligands for breast cancer.