Cerchia, Carmen (2016) IDENTIFICATION OF NOVEL INHIBITORS OF CDC25 PHOSPHATASES AS NEW ANTI-MELANOMA AGENTS BY LIGAND- AND STRUCTURE-BASED VIRTUAL SCREENING STUDIES. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: IDENTIFICATION OF NOVEL INHIBITORS OF CDC25 PHOSPHATASES AS NEW ANTI-MELANOMA AGENTS BY LIGAND- AND STRUCTURE-BASED VIRTUAL SCREENING STUDIES
Creators:
CreatorsEmail
Cerchia, Carmencarmen.cerchia@unina.it
Date: 31 March 2016
Number of Pages: 95
Institution: Università degli Studi di Napoli Federico II
Department: Farmacia
Scuola di dottorato: Scienze farmaceutiche
Dottorato: Scienza del farmaco
Ciclo di dottorato: 28
Coordinatore del Corso di dottorato:
nomeemail
D'Auria, Maria Valeriamadauria@unina.it
Tutor:
nomeemail
Lavecchia, AntonioUNSPECIFIED
Date: 31 March 2016
Number of Pages: 95
Uncontrolled Keywords: CDC25 phosphatases, Melanoma, Virtual Screening
Settori scientifico-disciplinari del MIUR: Area 03 - Scienze chimiche > CHIM/08 - Chimica farmaceutica
Date Deposited: 11 Apr 2016 08:43
Last Modified: 10 May 2017 01:00
URI: http://www.fedoa.unina.it/id/eprint/11040

Abstract

Cell division cycle 25 (CDC25) proteins are highly conserved dual specificity phosphatases that regulate the proper advancement of the cell cycle by activation of CDK/cyclin complexes. Overexpression of CDC25s, resulting in genomic instability and dysregulated cell growth, is frequently related to aggressiveness, high-grade tumors and poor prognosis. Thus, this family of enzymes represent an attractive target for drug discovery. Recently, compound 11, 3-(4,5,6-trihydroxy-3-oxo-3H-xanthen-9-yl)- propanoic acid, and compound 19, 4-(2-carboxybenzoyl)phthalic acid, were identified as novel inhibitors of CDC25s with a different inhibition profile, by using a structure-based virtual screening approach. Both compounds arrested cells at the G0/G1 and G2/M phases of the cell cycle, increased Cdk1 hyperphosphorylation in K562 leukemia cells, and significantly suppressed the growth of human MCF-7 breast, PC-3 prostate cancer lines as well as K562 leukemia cells, thus representing novel interesting leads. This thesis project focused on the computer-assisted lead optimization of the initial hits 11 and 19. Firstly, in order to expand our understanding of structure-activity relationships within the 6-xanthone class of CDC25 inhibitors, we identified a series of structural analogs of compound 11 by ligand-based chemoinformatic approach. We examined their activity against melanoma cancer cell lines, as well as the mechanism of action involved. Nine compounds (3, 5–9, 21, 24, and 25) were identified with Ki values for CDC25A, -B and -C ranging from 0.01 to 4.4 μM. One of these analogs, 7, showed a high antiproliferative effect on human melanoma cell lines, A2058 and SAN, associated with an arrest in G2/M phase of the cell cycle. Furthermore, 7 induced apoptosis through intrinsic pathway. Interestingly, compound 7 decreased the protein levels of phosphorylated Akt and increased those of p53, thus contributing to the regulation of chemosensitivity through the control of downstream Akt pathways in melanoma cells. Secondly, a series of novel derivatives of compound 19 was rationally designed by using a structure-based approach, guided by preliminary docking studies, with the aim to improve its binding affinity, pharmacokinetic properties as well as to investigate its anti-melanoma effect. A focused library of 24 derivatives was synthesized: a preliminary screening of the inhibitory activities toward CDC25B showed that ten molecules (compounds 2, 3d, 4, 4a, 4b, 5f, 6, 6a, 6b, 7) acted as powerful inhibitors with Ki values ranging between 2.8–20.1 μM. Among them, compounds 2 and 6a showed good antiproliferative effects on melanoma cell line A2058. Taken together, our data emphasize that CDC25 could be considered as a possible oncotarget in melanoma cells and that the designed compounds represent small molecule CDC25 inhibitors that merit to be further evaluated as chemotherapeutic agents for melanoma, likely in combination with other therapeutic compounds.

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