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Novel drug candidates to treat non-small cell lung cancer: lead optimization and development of CTP:phosphoethanolamine cytidylyltransferase inhibitors

Grant number: 17/22837-0
Support Opportunities:Research Grants - Innovative Research in Small Business - PIPE
Duration: October 01, 2018 - December 31, 2020
Field of knowledge:Health Sciences - Medicine
Convênio/Acordo: Centro para el Desarrollo Tecnológico Industrial (CDTI)
Principal Investigator:Kerly Fernanda Mesquita Pasqualoto
Grantee:Kerly Fernanda Mesquita Pasqualoto
Host Company:Alchemy Inovação, Pesquisa e Desenvolvimento Ltda
CNAE: Pesquisa e desenvolvimento experimental em ciências físicas e naturais
City: Santana de Parnaíba
Associated researchers:Alcindo Aparecido dos Santos ; Gizele Celante ; Marcos Felipe Pinatto Botelho ; Ricardo Alexandre de Azevedo ; Salomão Dória Jorge


Non-small cell lung cancer (NSCLC) is the most common type of lung cancer accounting for about 85% of all lung cancer cases. Its 5-year survival rate remains at approximately 17%. Almost half of cases have locally advanced or widespread metastasis at diagnosis. In addition, it is therapeutically limited. Despite the successful use of small molecule inhibitors, a major problem reminiscent in the treatment of advanced disease is due to those patients resistant to the current chemotherapeutics. Therefore, it is of utmost need the development of new drug candidates, efficient and selective, to provide a better prognosis for the patients. The enzyme CTP: phosphoethanolamine cytidylyltransferase (also called ethanolamine-phosphate cytidylyltranferase 2, Pcyt-2) catalyzes a crucial step in phosphatidylethanolamine (PE) synthesis, known as the Kennedy pathway, and uses phophoethanolamine as a substrate. PE is a major phospholipid in the cell membrane. Reduction of PE levels in tumor cells either by blocking endogenous processes, or by using chemical inhibitors, may affect the cell division, apoptosis, and autophagy. That, in turn, affects the cellular bioenergetics, eventually triggering death by apoptosis, and impairing lipids signaling, which is directly associated with the regulation of mitogen-activated protein kinase (MAPKs) mediated signaling pathways. Thus, the inhibition of PE synthesis may constitute a promising strategy for the identification of novel antitumor compounds against lung cancer. We have recently developed a small molecule, named CHY-1, as potential anticancer drug candidate against lung cancer. Concerning the experimental findings, CHY-1 can be considered as a new prototype for Pcyt-2 inhibition, presenting cytotoxic effects against NSCLC. Most importantly, CHY-1 blocks Pcyt-2 leading to the reduction of PE intracellular levels. Also, it reduces autophagy flux in the H460 and A549 cell lines, which is a remarkable effect. In addition, CHY-1 produces an endoplasmic reticulum (ER) stress leading to the activation of unfolded protein response (UPR) systems. Besides these in vitro findings, CHY-1 has reduced the tumor volume in NSCLC animal model. Thus, as the technological feasibility regarding CHY-1 has been provided, it can be considered as a prototype/lead compound to follow the step of lead optimization for developing novel drug candidates to treat NSCLC. The lead compound was conceived based on a well-established, interactive, and multidisciplinary process, regarding the development and structural optimization of a template, integrating computer-aided drug design (CADD), organic chemistry, and pharmacological evaluation (biological assays in vitro and in vivo). In PIPE Phase II, the steps of lead optimization for Pcyt-2 inhibition, synthesis of promising novel lead compounds, synthesis scale-up, and pharmacological evaluation in vitro and in vivo, will be carried out to find new chemical entities (NCE) to treat NSCLC. The scaling-up of synthesis regarding optimized leads may provide the NCE's production feasibility. Among in vitro proofs of concept (POC) will be the NCE's inhibitory activity in Pcyt-2. Animal model of lung cancer will be also considered to generate in vivo POC. Moreover, non-regulatory in vivo studies will be carry out to evaluate the NCE's toxicological profile. At the end of 24 months, after synthesis scale-up and antitumor activity validation, the intellectual property concerning the early phase of development of the novel drug candidates to treat NSCLC can be protected and negotiated with a third party. (AU)

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