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Development of Pet-1 as a small molecule inhibitor of the CDP- ethanolamine Kennedy pathway with therapeutic potential for Non- Small Cell Lung Cancer

Grant number: 22/01988-9
Support Opportunities:Research Grants - Innovative Research in Small Business - PIPE
Duration: February 01, 2023 - January 31, 2025
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Adilson Kleber Ferreira
Grantee:Adilson Kleber Ferreira
Host Company:Alchemypet Medicina Diagnóstica e Veterinária Ltda
CNAE: Atividades de serviços de complementação diagnóstica e terapêutica
City: São Paulo
Associated researchers: Frank Adrianus Eli Kruyt ; Marica Bakovic ; Roger Chammas
Associated scholarship(s):23/02508-3 - Development of Pet-1 as a small molecule inhibitor of the CDP- ethanolamine Kennedy pathway with therapeutic potential for Non- Small Cell Lung Cancer, BP.PIPE

Abstract

Lung cancer is one of the most lethal cancers in the world, and development of new drugs is essential for the control of this disease. The most abundant phospholipid in the inner cell membranes is phosphatidylethanolamine (PE), which is essential for the cell growth, cytokinesis, apoptosis and autophagy. The main route of PE synthesis by the CDP ethanolamine Kennedy pathway is regulated by CTP: phosphoethanolamine cytidylyltransferase (Pcyt-2). In the lung tissue, samples of non-small cell lung cancer (NSCLC) patients commonly have increased PE levels when compared to non-malignant lung samples. The inhibition of phosphatidylethanolamine (PE) synthesis can stop the cell division by preventing the correct processing of cytokinesis and induces a topological impairment of the transmembrane protein domains, mainly those in mitochondria. Interfering with membrane PE synthesis is an attractive novel strategy for rational drug design in lung cancer. Previously, we validated the Pcyt-2 as a new targeting in lung cancer, based on CRISPR/Cas9 technology. Pcyt-2 was knocked is lung cancer cells by, which could block cell growth in vitro and in vivo. Once target validation studies have been completed, the hit identification and lead discovery stages of the preclinical drug discovery process was continued. We have recently developed a small molecule (hit), named CHY- 1, as a potential anticancer drug candidate against lung cancer. Importantly, CHY-1 could block Pcyt-2 leading to the reduction of PE intracellular levels. Interestingly, CHY-1 also reduced autophagy flux in the H460 and A549 lung cancer cells. In addition, CHY-1 produces an endoplasmic reticulum (ER) stress leading to the activation of unfolded protein response (UPR) systems and increased immunogenicity of tumor cells both in vitro and in vivo. Importantly, CHY-1 reduced the tumor growth in a NSCLC xenograft mouse. These data qualify CHY-1 as a novel inhibitor of PCYT2 and the CDP-ethanolamine Kennedy pathway operating through multiple mechanisms for cell death including the inhibition of autophagy, the induction of ER stress and the immunogenic cell death. Thus, we demonstrated the technological feasibility of developing Pcyt-2 targeting drugs and CHY-1 can be considered as a prototype compound for lead optimization for developing novel drug candidates to treat NSCLC. As the final stage in the preclinical drug discovery process, the main goal of the lead optimization phase is to maintain the desired properties of the drug's main components, to improve their selectivity and specificity to Pcyt2. Thus, In the present study, we will synthesize a new antitumor lead, a phospholipid ether derivative named Pet-1, as a novel inhibitor of Pcyt2 and the CDP-ethanolamine Kennedy pathway. The lead compound (Pet-1) 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). Overall, this project aims to conduct the lead optimization of Pet-1 as a Pcyt-2 inhibitor, synthesis (drug file), synthesis scale-up, and pharmacological evaluation in vitro and in vivo. A highlight of this study is the evaluation of Pet-1 effects using the lung-on-a-chip as a proof-of-concept. This human "breathing lung-on-a-chip" microdevice provides the capabilities to reconstitute three-dimensional microarchitecture, dynamic mechanical activity, and integrated physiological function of the alveolar-capillary interface. Thus, this in vitro toxicological and pharmacological assay increases the likelihood of a correct prediction of Pet-1 in vivo effects. (AU)

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