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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

Grant number: 15/18528-7
Support type:Research Grants - Young Investigators Grants
Duration: April 01, 2016 - March 31, 2020
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Adilson Kleber Ferreira
Grantee:Adilson Kleber Ferreira
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Assoc. researchers:Cristoforo Scavone ; Jose Alexandre Marzagão Barbuto ; Kerly Fernanda Mesquita Pasqualoto ; Liliana Marzorati ; Marcio Henrique Zaim
Associated scholarship(s):17/13686-9 - Rational design of a sting agonist as a model for the implementation of a platform for the development of new immunotherapies against cancer, BP.PD
17/00497-3 - 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, BP.MS
16/09392-7 - Validation of CTP:phosphoethanolamine cytidylyltransferase enzyme and ethanolamine transport as new targets for the rational development of new drugs in non-small cell lung cancer treatment, BP.DR
16/07519-0 - Development of CHY-1 as a new drug candidate for the treatment of different types of breast cancer, BP.PD
16/05351-4 - 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, BP.JP

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 phophoethanolamine 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)

Scientific publications (6)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
GAITAN TABARES, JULIE PAULINE; SANTOS, RODRIGO LUIS S. R.; CASSIANO, JEFFERSON LUIZ; ZAIM, MARCIO H.; HONORATO, JOAO; BATISTA, ALZIR A.; TEIXEIRA, SARAH F.; FERREIRA, ADILSON KLEBER; VIANA, ROMMEL B.; MARTINEZ, SANDRA QUISPE; STABILE, ANTONIO CARLOS; SILVA, DENISE DE OLIVEIRA. A Ru(II)-p-cymene compound bearing naproxen-pyridineamide. Synthesis, spectroscopic studies, computational analysis and in vitro anticancer activity against lung cells compared to Ru(II)-p-cymene-naproxen and the corresponding drug ligands. Inorganica Chimica Acta, v. 489, p. 27-38, APR 1 2019. Web of Science Citations: 0.
MAMBELLI, LISLEY I.; TEIXEIRA, SARAH F.; JORGE, SALOMAO D.; KAWAMURA, BARBARA; MENEGUELO, RENATO; BARBUTO, JOSE A. M.; DE AZEVEDO, RICARDO A.; FERREIRA, ADILSON K. Phosphoethanolamine induces caspase-independent cell death by reducing the expression of C-RAF and inhibits tumor growth in human melanoma model. BIOMEDICINE & PHARMACOTHERAPY, v. 103, p. 18-28, JUL 2018. Web of Science Citations: 1.
TEIXEIRA, SARAH F.; RODRIGUES, CECILIA P.; COSTA, CICERO J. S.; PETTINATI, THAIS N.; DE AZEVEDO, RICARDO A.; MAMBELLI, I, LISLEY; JORGE, SALOMAO D.; RAMOS, RODRIGO N.; FERRO, EMER S.; BARBUTO, JOSE A. M.; FERREIRA, ADILSON K. Edelfosine: An Antitumor Drug Prototype. ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY, v. 18, n. 6, p. 865-874, 2018. Web of Science Citations: 0.
FERREIRA, ADILSON K.; MAMBELLI, LISLEY I.; PILLAI, SARAVANAN Y. Intervening in disease through genetically-modified bacteria. BEST PRACTICE & RESEARCH IN CLINICAL GASTROENTEROLOGY, v. 31, n. 6, p. 693-697, DEC 2017. Web of Science Citations: 0.
DE SA JUNIOR, PAULO LUIZ; DIAS CAMARA, DIANA APARECIDA; PORCACCHIA, ALLAN SAJ; MOREIRA FONSECA, PAMELA MARIA; JORGE, SALOMAO DORIA; ARALDI, RODRIGO PINHEIRO; FERREIRA, ADILSON KLEBER. The Roles of ROS in Cancer Heterogeneity and Therapy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY, 2017. Web of Science Citations: 16.
TEIXEIRA, SARAH FERNANDES; DE AZEVEDO, RICARDO ALEXANDRE; SILVA, ARTHUR CARVALHO; BRAGA, RODOLPHO CAMPOS; JORGE, SALOMAO DORIA; MARZAGAO BARBUTO, JOSE ALEXANDRE; ANDRADE, CAROLINA HORTA; FERREIRA, ADILSON KLEBER. Evaluation of cytotoxic effect of the combination of a pyridinyl carboxamide derivative and oxaliplatin on NCI-H1299 human non-small cell lung carcinoma cells. BIOMEDICINE & PHARMACOTHERAPY, v. 84, p. 1019-1028, DEC 2016. Web of Science Citations: 1.

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