STRUCTURAL ANALYSIS, RATIONAL DESIGN, AND OPTIMIZATION OF NOVEL MICROTUBULE TARGETING AGENTS.

Microtubule targeting agents represent a significant class of drugs, with currently more than 20 approved formulations utilized in anti-inflammatory, anti-infective, and predominantly anti-cancer therapies. These agents interact with a,b-tubulin heterodimers within microtubules, impacting their dynamic behavior which is crucial in cellular processes like signaling, transport, or cell division. Despite the extensive range of molecules studied and trialed, central challenges in their therapeutic application remain, such as high toxicity, particularly neuropathies, low efficacy at tolerable doses as well as drug resistance. Efforts to address these issues include the characterization of new binding sites and molecules which demonstrate exceptional activity in resistant cell lines. This thesis contributes to this ongoing research, focusing on the structural characterization of maytansine-site ligands and the design of ligands for the Todalam site.