Full text
| |
| Author(s): |
Renna Karoline Eloi Costa
Total Authors: 1
|
| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia |
| Defense date: | 2021-09-24 |
| Examining board members: |
Sandra Martha Gomes Dias;
Paulo Henrique Conaggin Godoi;
Carolina Borsoi Moraes;
Catarina Raposo Dias Carneiro;
Eduardo Henrique Salviano Bezerra
|
| Advisor: | Sandra Martha Gomes Dias |
| Abstract | |
Breast cancer is the most diagnosed type of cancer in women, with an estimated incidence of approximately 3.2 million cases per year until 2050. The triple negative subtype (Triple Negative Breast Cancer, TNBC), characterized by low expression/ non-detection of estrogen hormone receptors (ER), progesterone (PR) and growth factors (Her2), is the most common among young women, having the characteristics of being more aggressive, larger, more likely to metastasize and have a worse prognosis with greater chances of recurrence. Metabolic reprogramming in tumor cells may provide targets for cancer treatment. Among them, the activation of glycolysis (even in the presence of oxygen) stands out, with an increase in lactate secretion and cataplerosis of the tricarboxylic acid cycle (Tricarboxylic acid cycle, TCA) to provide important intermediary biosynthetic pathways. In the triple-negative subtype specifically, the enzyme glutaminase, encoded by GLS, the first in the pathway of metabolization of the amino acid glutamine and an important anaplerotic source of TCA, was described as a target for treatment. GLS encodes, by alternative splicing, glutaminase C (GAC) and kidney-type glutaminase (KGA). IPN60090 and CB-839 are GLS inhibitors in phase I and II clinical trials, respectively, in solid (such as triple-negative breast) and hematologic tumors. A few years ago, our laboratory carried out two campaigns using a High Throughput Screening (HTS) biochemical assay, one with a library of 30,000 synthetic compounds (Chembridge) and the other with 728 drugs approved by the US Food and Drug Administration (FDA). A cell assay was also previously performed in the laboratory using cell lineage with GLS expression or gene knock down to evaluate extracts and fractions of natural products. Some of the hits identified in these campaigns were the study targets of this thesis. Idebenone, an analogue of ubiquinone (coenzyme Q10), evaluated in the treatment of Alzheimer's and neuromuscular diseases and now approved for use in Leber's hereditary optic neuropathy, has been shown to be a tumor-acting inhibitor of GLS, GLS2 and glutathione dehydrogenase. Forty-six hits from the HTS campaign were acquired and 3 of them, called C9, C12, C15, in addition to molecules with a triazole functional group, were explored in this thesis. Screening with natural products did not reveal any compounds with GLS inhibitory activity. Structure-function studies of small hit molecules revealed analogues of greater potency and cell selectivity. In focus, we identify a C9 derivative, C9.22, with an innovative structural scaffold and describe the molecular determinants of its inhibitory activity (AU) | |
| FAPESP's process: | 16/09077-4 - Developing new glutaminase inhibitors with potential anti-tumor activity |
| Grantee: | Renna Karoline Eloi Costa |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |