PM534, 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 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.