biostudies-literatureLucena-Agell DMinisterio de Ciencia e InnovaciónFundación Tatiana Pérez de Guzmán el BuenoEuropean CommissionPharmaMar2619-2630https://www.ebi.ac.uk/biostudies/studies/S-EPMC10895673biostudies-literatureUnknown67(4)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 <i>order Lithistida</i>, family <i>Theonellidae</i>, genus <i>Discodermia</i> (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). FurtheJournal of medicinal chemistryPM534, an Optimized Target-Protein Interaction Strategy through the Colchicine Site of Tubulin.PMC10895673PID2022-136765OB-I00PID2021-123399OB-I00PID2020-117580RB-I00Martinez-Diez MHortiguela RPlaza-Menacho IGimenez-Abian JFLucena-Agell DOliva MAAviles PSantamaria-Nunez GCuevas CGuillen MJMatesanz RDiaz JFAlvarez-Bernad BContreras JfalsePM534, an Optimized Target-Protein Interaction Strategy through the Colchicine Site of Tubulin.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 <i>order Lithistida</i>, family <i>Theonellidae</i>, genus <i>Discodermia</i> (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). Furthe2024-01-01T00:00:00Z2024 Feb2026-05-29T12:34:03.861Z2025-02-19T01:42:02.224ZS-EPMC108956733829434110.1021/acs.jmedchem.3c01775