PM534, a Novel Colchicine Site Tubulin Inhibitor with Broad-Spectrum and Resistance-Overcoming Antitumor Activity.

This study evaluates PM534, a novel colchicine-binding domain inhibitor, for its potential in cancer therapy. PM534 exhibited potent in vitro efficacy against a panel of 14 human cancer cell lines, including breast, ovarian, and prostate cancers, with concentration needed to reduce the growth of treated cells to half that of untreated cells values in the low nanomolar range. Both continuous (72 hours) and short-term (1-24 hours) exposure led to irreversible effects, inducing G2-M cell cycle arrest and multinucleation. Additionally, PM534 also impaired angiogenic process. It effectively inhibited HUVEC functions, including adhesion, with an IC50 of 2.3 nmol/L, markedly more potent than colchicine (IC50 = 1,800 nmol/L). At concentrations as low as 1.6 nmol/L, PM534 delayed wound closure in migration assays, completely inhibiting migration above 4 nmol/L. Additionally, PM534 abrogated invasion and disrupted capillary-like network formation at concentrations starting from 0.5 nmol/L without inducing cytotoxicity. In vivo PM534 demonstrated robust antitumor efficacy across six xenograft models, including ovarian (A2780 and ES-2), triple-negative breast (MDA-MB-231 and HCC1937), and prostate (VCaP and 22Rv1) tumors. This treatment also led to statistically significant increases in median survival times across all models, without inducing signs of systemic toxicity. Mechanistically, PM534 induced apoptosis, mitotic catastrophe, and necrosis in tumor tissues. Importantly, PM534 retained efficacy in models overexpressing multidrug resistance proteins P-glycoprotein or β-III tubulin, overcoming common resistance mechanisms that limit the effectiveness of other tubulin-binding agents. Collectively, these findings highlight PM534 as a promising antitumor agent with potent activity against diverse and treatment-resistant malignancies. A phase I clinical trial (NCT#5835609) is underway to assess the therapeutic potential of PM534 in patients with advanced solid tumors.