Download MendeleyPM534, an Optimized Target-Protein Interaction Strategy through the Colchicine Site of Tubulin.
Lucena-Agell, D., Guillen, M.J., Matesanz, R., Alvarez-Bernad, B., Hortiguela, R., Aviles, P., Martinez-Diez, M., Santamaria-Nunez, G., Contreras, J., Plaza-Menacho, I., Gimenez-Abian, J.F., Oliva, M.A., Cuevas, C., Diaz, J.F.(2024) J Med Chem 67: 2619-2630
- PubMed: 38294341
- DOI: https://doi.org/10.1021/acs.jmedchem.3c01775
- Primary Citation of Related Structures:
7ZYW - PubMed Abstract:
Targeting microtubules is the most effective wide-spectrum pharmacological strategy in antitumoral chemotherapy, and current research focuses on reducing main drawbacks: neurotoxicity and resistance. PM534 is a novel synthetic compound derived from the Structure-Activity-Relationship study on the natural molecule PM742, isolated from the sponge of the order Lithistida , family Theonellidae , genus Discodermia (du Bocage 1869). PM534 targets the entire colchicine binding domain of tubulin, covering four of the five centers of the pharmacophore model. Its nanomolar affinity and high retention time modulate a strikingly high antitumor activity that efficiently overrides two resistance mechanisms in cells (detoxification pumps and tubulin βIII isotype overexpression). Furthermore, PM534 induces significant inhibition of tumor growth in mouse xenograft models of human non-small cell lung cancer. Our results present PM534, a highly effective new compound in the preclinical evaluation that is currently in its first human Phase I clinical trial.
Organizational Affiliation:
Unidad BICS. Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain.
