Structural and molecular bases of inhibitor recognition by the CDC-25 and LMW-PTP human protein phosphatases involved in cancer

• Grant number: 10/17544-5
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): March 01, 2011
• Effective date (End): January 31, 2013
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Ronaldo Aloise Pilli
• Grantee: Daniela Barretto Barbosa Trivella
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated scholarship(s): 11/21358-5 - Screening of (bio)synthetic organic compounds with biological targets against cancer, BE.EP.PD

Abstract

Cancer is the second non-accidental cause of death in Brazil, where the annual governmental expenses with this pathology are around 1 billion Reais. In many cases, anticancer treatment and therapies fail, being of extremely important the development of new therapies or the improvement of the existent ones. The design of activity modulators of tumor overexpressed proteins is one of the main research areas in this direction. In particular, CDC-25 and LMW-PTP protein phosphatases were identified as important targets for anticancer therapy development. These proteins are involved in cell signaling and are overexpressed in several types of malignant tumors. In this direction, the present project aims at evaluating the inhibition capacity of CDC-25 and LMW-PTP activity by new families of chemical compounds synthesized as part of the Thematic Project "Biologia Química: novos alvos moleculares naturais e sintéticos contra o câncer. Estudos estruturais, avaliação biológica e modo de ação" (Fapesp 2009/51602-5), as well the characterization of the interaction of the identified inhibitors with these phosphatases, through a biochemical, structural and thermodynamic approach. The results to be obtained will help to understand the molecular bases of inhibitor interaction and selectivity to the investigated protein phosphatases, giving support to new structures design/ modification and, therefore, improving their potency and/or selectivity in inhibiting the selected protein phosphatases. In this direction, the present research propose will contribute to the incorporation of receptor structure based rational drug design tools to the associated Thematic Project. (AU)

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, AUG 1 2015. (10/17544-5, 11/03054-9, 09/51602-5, 11/15792-4)

CARNEIRO, VANIA M. T.; TRIVELLA, DANIELA B. B.; SCORSATO, VALERIA; BERALDO, VIVIANE L.; DIAS, MARIANA P.; SOBREIRA, TIAGO J. P.; APARICIO, RICARDO; PILLI, RONALDO A.. Is RK-682 a promiscuous enzyme inhibitor? Synthesis and in vitro evaluation of protein tyrosine phosphatase inhibition of racemic RK-682 and analogues. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 97, p. 42-54, JUN 5 2015. (11/00457-5, 10/17544-5, 09/51602-5, 13/07607-8)

TONETO NOVAES, LUIZ FERNANDO; AVILA, CAROLINA MARTINS; PELIZZARO-ROCHA, KARIN JULIANE; VENDRAMINI-COSTA, DEBORA BARBOSA; DIAS, MARINA PEREIRA; BARBOSA TRIVELLA, DANIELA BARRETO; DE CARVALHO, JOAO ERNESTO; FERREIRA-HALDER, CARMEN VERISSIMA; PILLI, RONALDO ALOISE. (-)-Tarchonanthuslactone: Design of New Analogues, Evaluation of their Antiproliferative Activity on Cancer Cell Lines, and Preliminary Mechanistic Studies. CHEMMEDCHEM, v. 10, n. 10, p. 1687-1699, OCT 2015. (10/17544-5, 12/09254-2, 13/08896-3, 09/51602-5, 12/24385-6, 10/08673-6)