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New inhibitors of LMW-PTP and CDC25B: fragment-based drug design using in silico methods, inhibition assays and Protein Crystallography

Grant number: 11/15792-4
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): January 01, 2013
Effective date (End): January 31, 2015
Field of knowledge:Biological Sciences - Biophysics - Molecular Biophysics
Principal Investigator:Ricardo Aparicio
Grantee:Emanuella Maria Barreto Fonseca
Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil


Cancer is the common term used to designate a large class of diseases, including malignant tumors in different locations in the body. The increasing number of cases emerges today as a major public health problem. World Health Organization data on cancer incidence, mortality and prevalence worldwide reveals an alarming increasing, with 15 million new cases predicted for 2020 compared to 10 million cases in the year 2000, when nearly 25 million persons were living with cancer. Almost half of the new cases and two-thirds of the cancer deaths are expected to occur in low-income and developing countries like Brazil, where government funds for treatment of the disease exceed 1 billion reals per year. The current status of cancer therapy is characterized by very expansive treatments and low therapeutic index, thus being extremely important to develop new and better cancer therapies, one of the most important strategies being the development of modulators of the activity of proteins overexpressed in tumors. Particularly, the protein phosphatases CDC-25 and LMW-PTP, involved in critical cell signaling pathways and overexpressed in malignant tumors, have been identified as important targets for developing new anticancer therapies. The aim of this project is to use a fragment-based approach to develop inhibitors of CDC-25 and LMW-PTP, starting from chemical databases, through the integrated use of in silico methods and Protein Crystallography. The results obtained will contribute significantly to identify novel inhibitors toward a broader diversity of molecular scaffolds, leading to a deeper understanding of molecular recognition by the targeted phosphatases, an essential knowledge for developing lead compounds as candidate drugs for cancer treatment.

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Scientific publications
(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)
FONSECA, EMANUELLA M. B.; TRIVELLA, DANIELA B. B.; SCORSATO, VALERIA; DIAS, MARIANA P.; BAZZO, NATALIA L.; MANDAPATI, KISHORE R.; DE OLIVEIRA, FABIO L.; FERREIRA-HALDER, CARMEN V.; PILLI, RONALDO A.; MIRANDA, PAULO C. M. L.; et al. Crystal structures of the apo form and a complex of human LMW-PTP with a phosphonic acid provide new evidence of a secondary site potentially related to the anchorage of natural substrates. Bioorganic & Medicinal Chemistry, v. 23, n. 15, p. 4462-4471, . (10/17544-5, 11/03054-9, 09/51602-5, 11/15792-4)
PEREIRA MACHADO, AGNES THIANE; BARRETO FONSECA, EMANUELLA MARIA; DOS REIS, MARCELO AUGUSTO; SARAIVA, ANTONIO MARCOS; DOS SANTOS, CLELTON APARECIDO; SZYMANSKI DE TOLEDO, MARCELO AUGUSTO; POLIKARPOV, IGOR; DE SOUZA, ANETE PEREIRA; APARICIO, RICARDO; IULEK, JORGE. Conformational variability of the stationary phase survival protein E from Xylella fastidiosa revealed by X-ray crystallography, small-angle X ray scattering studies, and normal mode analysis. PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, v. 85, n. 10, p. 1931-1943, . (12/51580-4, 11/15792-4)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
FONSECA, Emanuella Maria Barreto. New inhibitors of LMW-PTP and CDC25B: fragment-based drug design using in silico methods, inhibition assays and protein crystallography. 2015. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Instituto de Química Campinas, SP.

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