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

EVELYN AREL ZALAZAR; CARLA M. BORINI ETICHETTI; MARIA SOL BALLARI; NABILA COCORDANO; GUILLERMO R. LABADIE; JAVIER GIRARDINI

Mar del Plata

Congreso; Reunión Anual de Sociedades de Biociencias; 2022

ICMT (Isoprenylcysteine Carboxymethyl Transferase) is involvedin the posttranslational modification process known as prenylation,which starts with the addition of an isoprenoid to a cysteine near theC-terminus, followed by the cleavage of terminal amino acids. Then,ICMT catalyzes the methylation of the newly generated C-terminuson the cysteine. This modification, regulates critical functional aspects of substrate proteins. ICMT has emerged as an interestingtarget for novel anti-cancer therapies. We have previously shownthat 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 moleculewas reported to inhibit ICMT and recently has reached clinical trialsfor the treatment of Non Small Cel Lung Carcinoma (NSCLC). Weanalyzed the effects of a collection of 27 compounds on cell viabilityusing H1299 (NSCLC) and MDA-MB-231 (Triple Negative BreastCancer) cells. Through bioreduction-based assays we identified fourcompounds showing significant activity (p < 0,02; n=3). Among compounds which did not affect cell viability we analyzed the ability toreduce metastasis associated phenotypes such as migration andinvasion. We performed wound healing assays on the H1299 cellline. Our results showed that four compounds significantly inhibitedcell 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-coatedfilters. We found that two of them significantly reduced invasion invitro (p= 0.0009; p= 0.0158 n=3). In summary, we identified novelSalirasib derivatives that reduced cancer-associated phenotypes in vitro and are interesting candidates for leading molecules in cancertherapy