Over the past sixty years, microtubule-targeting agents have demonstrated a great success in their employment in cancer treatment, both alone and in combination with other drugs. However, two significant drawbacks limit their clinical application. Firstly, their toxic side effects, primarily neurotoxicity and neutropenia that block the use of these drugs in several cycles of chemotherapy. Secondly, the rise of resistances through different mechanisms like the overexpression of membrane pumps and, the differential expression of specific tubulin isotypes, which urge to find new compounds capable to override these problems. In addition to their relevance in cancer biology and chemotherapy, microtubules are used by certain viruses as intracellular platforms to facilitate their viral life cycle. Based on this, we proposed the use of these compounds as antiviral agents in a study published in 2022. From that study, ligands that bind to the colchicine site emerged as potential candidates to inhibit de infectivity of some viruses, indicating that the colchicine site’s mechanism of action on tubulin is relevant for this purpose. Here, we present a collaborative effort with the pharmaceutical company PharmaMar to develop PM534, a colchicine site binder with potent antitumor properties. Through cell biology, mouse xenografts, biochemical assays, and structural analysis, we have characterized the relevance of this compound as a microtubule-targeting agent. PM534 binds to the full colchicine site in tubulin, occupying four of the five centers in the pharmacophore model. Its nanomolar affinity, extended dwelling time, and ability to overcome the two distinct mechanisms of resistance underscore its exceptional potential. Furthermore, PM534’s significant growth-inhibitory effects over non-small cell lung cancer xenografts in mice demonstrate high efficacy in preclinical evaluation. In summary, PM534 is a promising new drug currently undergoing its first human Phase I clinical trial.

Peer reviewed

1 p.