TARGETING THE PRENYLATION PATHWAY IN CANCER: IDENTIFICATION AND CHARACTERIZATION OF NOVEL SALIRASIB DERIVATIVES

AREL ZALAZAR, EVELYN; BORINI ETICHETTI, CARLA M; BALLARI, MS; CERRI, AGUSTINA; COCORDANO, NABILA; LABADIE, GUILLERMO; GIRARDINI, JAVIER

Congreso; REUNIÓN CONJUNTA SAIC SAI&FAIC SAFIS 2022; 2022

ICMT (Isoprenylcysteine Carboxymethyl Transferase) is involved in the posttranslational modification process known as prenylation, which starts with the addition of an isoprenoid to a cysteine near the C-terminus, followed by the cleavage of terminal amino acids. Then, ICMT catalyzes the methylation of the newly generated C-terminus on the cysteine. This modification, regulates critical functional aspects of substrate proteins. ICMT has emerged as an interesting target for novel anti-cancer therapies. We have previously shown that ICMT enhances aggressive tumor phenotypes and that its expression is repressed by the p53 tumor suppressor. In order to identify novel ICMT inhibitors we generated derivatives of Farnesylthiosalisilic acid (FTS), commercially known as Salirasib. This molecule was reported to inhibit ICMT and recently has reached clinical trials for the treatment of Non Small Cel Lung Carcinoma (NSCLC). We analyzed the effects of a collection of 27 compounds on cell viability using H1299 (NSCLC) and MDA-MB-231 (Triple Negative Breast Cancer) cells. Through bioreduction-based assays we identified four compounds showing significant activity (p < 0,02; n=3). Among compounds which did not affect cell viability we analyzed the ability to reduce metastasis associated phenotypes such as migration and invasion. We performed wound healing assays on the H1299 cell line. Our results showed that four compounds significantly inhibited cell migration (p= 0.0009; 8: p= 0.0017; 9: p= 0.0003; 13: p= 0.0202; n=3). To further characterize these compounds, we tested their effect on invasion by transwell invasion assays using Matrigel-coated filters. We found that two of them significantly reduced invasion in vitro (p= 0.0009; p= 0.0158 n=3). In summary, we identified novel Salirasib derivatives that reduced cancer-associated phenotypes in vitro and are interesting candidates for leading molecules in cancer therapy.