Abstract 6243: The novel antitubulin agent PM534 exhibits potent antitumoral and antiangiogenic properties in vitro and in vivo

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Abstract Background: Microtubule targeting agents have demonstrated to be very effective antitumoral drugs. The development of novel anti-tubulin agents with more efficient mechanisms of action presents several challenges due to their poor solubility, troublesome synthesis or purification, and toxicities. In this work, we present the novel anti-tubulin agent PM534, a synthetic small molecule that shows efficient antitumoral and antiangiogenic properties in vitro and in vivo. Methods and Results: PM534 exhibits a potent antitumor activity in vitro with a mean GI50 value in the low nanomolar range in several different human cancer cell lines. Washout in vitro experiments show irreversible cellular effects after 1h in contact with the compound, compelling the cells to apoptotic cell death likely due to PM534 induced disorganization of the tubulin cytoskeleton. PM534 inhibits migration and invasion of tumor cells in vitro, and arrests the cell cycle in the G2/M phase, forcing them to apoptosis. In addition, PM534 presents potent antiangiogenic effects in vitro, robustly inhibiting endothelial cells proliferation and migration, and the formation of angiotubes. The in vivo antitumor activity of PM534 was characterized in human-derived tumors xenografted in athymic nu/nu mice, namely breast (MDA-MB-231), and pancreas (Mia-Paca-2). PM534 was intravenously administered once per week for three consecutive weeks at 5.0 mg/kg. In vivo PM534-induced antitumor activity (vs. placebo) was seen in MDA-MB-231 (T/C, 0.3% on Day 28; TV, p<0.0001) and Mia-Paca-2 (21.3% on Day 21; TV, p<0.0001). Also, PM534 treatment increased with statistical significance (vs. placebo) the median survival time of mice bearing MDA-MB-231 (82 vs. 33 days; p<0.0001) and Mia-Paca-2 (51 vs. 30 days; p=0.0008). Of note, complete tumor remissions were observed in 2/10 (lasting 11 days and 161 days, each), and 10/10 (lasting 45 days in 9/10 and 140 days in 1/10) PM534-treated animals bearing Mia-Paca-2 and MDA-MB-231 and tumors, respectively. Conclusions: Based on in vitro activity against different human tumor cell lines, in vivo activity in xenografted human tumors, as well as on its anti-angiogenic properties, the safety, pharmacology and preliminary antitumor activity of PM534 will be evaluated in a first-in-human clinical trial to be conducted in patients with advanced solid tumors. Citation Format: Marta Martínez Diez, María José Muñoz-Alonso, Gema Santamaría Nuñez, María José Guillén, María Ángela Oliva, Eva Maria Garrido-Martin, Pablo Avilés, J. Fernando Díaz, Carmen Cuevas. The novel antitubulin agent PM534 exhibits potent antitumoral and antiangiogenic properties in vitro and in vivo. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6243.

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