A new synthetic compound identified as a modulator of microtubules through the colchicine binding site

A study published in the journal J. Med. Chem and carried out by the group of the researcher J. Fernando Díaz at the Centro de Investigaciones Biológicas Margarita Salas (CSIC) in collaboration with Pharmamar S.A. has characterized a new synthetic compound, named PM534, with high antitumor activity demonstrated both in vivo and in vitro, making it a potential candidate for the treatment of refractory tumors.

Microtubule modulation is the most effective broad-spectrum pharmacological strategy in antitumor chemotherapy. Current research in this field is focused on reducing its main drawbacks: neurotoxicity and the emergence of resistance.

PM534 is a new synthetic compound derived from a structure-activity relationship study on the natural molecule PM742, isolated from the sponge of the order Lithistida, family Theonellidae, genus Discodermia. PM534 targets the entire colchicine-binding domain of tubulin, covering four of the five centers of the pharmacophore.

Lucena-Agell et al. demonstrate that the nanomolar affinity and high retention time of PM534 produce very high antitumor activity that efficiently overrides the two mechanisms of chemotherapy resistance in cells, detoxification pumps, and tubulin βIII isotope overexpression. In addition, PM534 induces significant tumor growth inhibition in mouse xenograft models of human non-small cell lung cancer.

PM534 is a highly effective compound, which is efficacious and safe in preclinical evaluation. The compound is currently in its first phase human clinical trial.

Reference: PM534, an optimized target protein interaction strategy through the colchicine site of tubulin. Daniel Lucena-Agell, María José Guillén, Ruth Matesanz, Beatriz Álvarez-Bernad, Rafael Hortigüela, Pablo Avilés, Marta Martínez-Díez, Gema Santamaría-Nuñez, Julia Contreras, Iván Plaza-Menacho, Juan F. Giménez-Abián, María A. Oliva, Carmen Cuevas and J. Fernando Díaz. J. Med. Chem. 2024. https://doi.org/10.1021/acs.jmedchem.3c01775