Design and synthesis of novel 4-aryl-2-benzoyl-imidazoles as colchicine binding site inhibitors.

Highly potent tubulin inhibitors serve as critical payloads in several FDA-approved antibody-drug conjugates (ADCs). However, all these compounds are natural products with complex structures, which limit the ability to adjust their physicochemical properties for the optimal balance between payload release and ADC stability during systemic circulation, as well as efficient tumor penetration. Although taxanes are widely used in cancer therapy, they are unsuitable for ADCs due to insufficient potency and a high tendency to develop acquired drug resistance. Colchicine binding site inhibitors (CBSIs) are attractive alternatives, offering tunable properties and the potential to overcome multidrug resistance associated with the use of many existing tubulin inhibitors. However, most CBSIs lack sufficient potency for viable ADC applications. In our pursuit of a highly potent CBSI suitable for ADC use, we identified a novel series of sabizabulin derivatives. These compounds were evaluated in vitro across four cancer cell lines, including one with high resistance to taxanes. Among them, compound 11b emerged as the most promising one with IC