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In silico studies and cell-based assays to identify new therapeutic approaches to prostate cancer

Grant number: 11/07025-3
Support type:Regular Research Grants
Duration: November 01, 2011 - October 31, 2013
Field of knowledge:Physical Sciences and Mathematics - Chemistry
Principal Investigator:Andrei Leitão
Grantee:Andrei Leitão
Home Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil

Abstract

The prostate cancer has the highest incidence among all neoplasia in middle-age men. This pathology is hormone-dependent, being androgen receptor (AR) the target of choice for antitumoral drugs bicalutamide, flutamide e nilutamide. However, the androgen-ablation therapy may not be efficacious at the late-phase disease, and it is necessary to introduce AR-independent bioactive compounds. In this case, some compounds that target the apoptotic process, being under clinical studies. This work aims to identify AR-dependent or AR-independent new chemical entities (NCEs) that inhibit the AR-signaling pathway, or by leading to cell death independently of AR (through the modulation of mTOR e survivin cell signaling) in order to identify new therapeutic approaches to prostate cancer. The rational drug discovery workflow is based on the ligand (LBVS) and structure (SBVS) virtual screenings using AR, surviving and mTOR, in conjunction with the prediction of pharmacokinetics properties. It is estimated that 30 to 40 molecules will be cherry-picked with the aid of the computational methods to be studied by cell-based assays. These compounds will be tested by flow cytometry to observe the phenotypic alterations of two cell models of prostate cancer (LNCaP and DU 145) regarding the intracellular granularity, in a HCS-type study, together with the analysis of the cell cycle arrest. All phenotypic alterations will lead to activity "fingerprints" observed to a selected reference set (composed by a mix of drugs and bioactive molecules). Structure-activity relationships (SAR) will be devised to optimize the compound series and to analyze the models and hypotheses established during the in silico step. The cell-based assays will be cornerstone to the application of polypharmacology and biochemical networks concepts at the forefront of the drug discovery process, with the aim of integrating the medicinal chemistry knowledge to exploit the chemical-biological space of prostate cancer. (AU)

Scientific publications (4)
(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)
GOMES, FRANCISCO E. R.; BERGO, PATRICIA L. S.; TRAP, MARILIA A.; SPADOTO, MARIANGELA; GALINARO, CARLOS A.; RODRIGUES-FILHO, EDSON; LEITAO, ANDREI; TREMILIOSI-FILHO, GERMANO. Photolysis of parabens using medium-pressure mercury lamps: Toxicity effects in MCF7, Balb/c 3T3 cells and Ceriodaphnia dubia. Chemosphere, v. 208, p. 325-334, OCT 2018. Web of Science Citations: 2.
SANTA CRUZ, ELISA C.; CARECHO, ADRIEL R.; SAIDEL, MARTA E.; MONTANARI, CARLOS ALBERTO; LEITAO, ANDREI. In silico selection and cell-based characterization of selective and bioactive compounds for androgen-dependent prostate cancer cell. Bioorganic & Medicinal Chemistry Letters, v. 27, n. 3, p. 546-550, FEB 1 2017. Web of Science Citations: 3.
MAY, ELEBEOBA E.; LEITAO, ANDREI; TROPSHA, ALEXANDER; OPREA, TUDOR I. A systems chemical biology study of malate synthase and isocitrate lyase inhibition in Mycobacterium tuberculosis during active and NRP growth. COMPUTATIONAL BIOLOGY AND CHEMISTRY, v. 47, p. 167-180, DEC 2013. Web of Science Citations: 5.
SOARES, FABYANA A.; SESTI-COSTA, RENATA; DA SILVA, JOAO SANTANA; DE SOUZA, MARIA CECILIA B. V.; FERREIRA, VITOR F.; SANTOS, FERNANDA DA C.; MONTEIRO, PATRICIA A. U.; LEITAO, ANDREI; MONTANARI, CARLOS A. Molecular design, synthesis and biological evaluation of 1,4-dihydro-4-oxoquinoline ribonucleosides as TcGAPDH inhibitors with trypanocidal activity. Bioorganic & Medicinal Chemistry Letters, v. 23, n. 16, p. 4597-4601, AUG 15 2013. Web of Science Citations: 17.

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