Development of new drug candidate for the treatment of non-small cell lung cancer: CHY-1 as a novel inhibitor of autophagy and prototype of a novel class of inhibitors of the enzyme CTP: phosphoethanolamine citidililtransferase

Abstract

Lung cancer is the leading cause of death from cancer worldwide. Chemotherapy protocols currently used for the treatment of non-small cell lung cancer (NSCLC) have still shown a limited response. Indeed, the resistance to chemotherapy remains the major problem for the treatment of advanced disease. In this regard, of utmost importance is the development of new, useful compounds that are efficient and selective, and that can possibly be used in the treatment of patients with lung cancer. CTP:phosphoethanolamine cytidylyltransferase (Pcyt-2) catalyzes a crucial step in phosphatidylethanolamine synthesis, known as the Kennedy pathway, and uses phophoethanol amine as a substrate. The inhibition of Pcyt-2 reduces the levels of a kind of zwitterionic glycerophospholipid named phosphatidylethanolamine (PE).In terms of species, PE is the second most abundant of phospholipids present in eukaryotic cells. Reduction of PE levels in tumor cells by blocking endogenous processes or with chemical inhibitors can affect the cell division, apoptosis and autophagy. Recently, we showed that Pcyt-2 is a potential target in lung cancer. Of great relevance, we have identified a new lead compound classified as (CHY-1). This compound has been used as a prototype for the rational development using (SBDD, structure-based drug design) of new potential inhibitors of Pcyt-2. Importantly, CHY-1 presents a higher selectivity for lung cancer cells such as H460, A549, NCI-H1299 and NCI-H292, and indeed it lacks hemolytic effects. It should be noted that in vivo CHY-1 has a large therapeutic window without showing signs of toxicity to mice. For the first time, we have demonstrated that CHY-1 blocks Pcyt-2 leading to reduction of intracellular PE levels, which in turn reduces the autophagy flux in NSCLC. In the current study we will elucidate more precisely the inhibitory effects of CHY-1 in the autophagy, a mechanism that remains unclear. To date, chloroquine and hydroxychloroquine, two well-known autophagy inhibitors, have been associated in clinical trials with standardized therapies for lung cancer treatment. Although this approach is considered a promising strategy, unfortunately these compounds induce serious toxicity. In this regard, it will be further evaluated whether there is an increase in antitumor efficacy without side effects by the therapeutic combination of CHY-1 with the antitumor agents cisplatin, taxol, and bevacizumab. Overall, the main goal of this proposal is the development of CHY-1 as a new prototype inhibitor of Pcyt-2. In parallel, we will investigate if these new compounds have the potential to become a new class of anticancer drugs. According to their synthetic feasibility, these new molecules will be synthesized and their potential antitumor effects will be evaluated in vitro and in vivo against NSCLC. (AU)