STARD3 is a cellular protein that represents an attractive target for cancer therapy, being overexpressed in breast cancer and implied in the development of colorectal, gastric, and prostate cancers. Unfortunately, no STARD3 inhibitor has been identified yet. In this work, an in silico strategy was applied to predict a reliable binding mode of cholesterol into STARD3 and to develop a pharmacophore-based virtual screening protocol that allowed the identification of the first STARD3 inhibitor ever reported. The identified compound VS1 binds STARD3 with micromolar affinity (IC 50 = 35 μM) and shows antiproliferative activity in breast (MCF7 and MDA- MB-231) and colon (HCT-116) cancer cell lines in the same concentration range (IC 50 = 49.7-105.5 μM). Although VS1 has a moderate potency, we demonstrated that it specifically targets STARD3 in the cells and induces its degradation. Overall, the results confirm the reliability of the computational strategies herein applied and the identification of the first hit compound for the development of novel potent STARD3 inhibitors.

First-of-its-kind STARD 3 Inhibitor: In Silico Identification and Biological Evaluation as Anticancer Agent

Lapillo M.
Primo
;
Poli G.;Granchi C.;Minutolo F.;Tuccinardi T.
;
2019-01-01

Abstract

STARD3 is a cellular protein that represents an attractive target for cancer therapy, being overexpressed in breast cancer and implied in the development of colorectal, gastric, and prostate cancers. Unfortunately, no STARD3 inhibitor has been identified yet. In this work, an in silico strategy was applied to predict a reliable binding mode of cholesterol into STARD3 and to develop a pharmacophore-based virtual screening protocol that allowed the identification of the first STARD3 inhibitor ever reported. The identified compound VS1 binds STARD3 with micromolar affinity (IC 50 = 35 μM) and shows antiproliferative activity in breast (MCF7 and MDA- MB-231) and colon (HCT-116) cancer cell lines in the same concentration range (IC 50 = 49.7-105.5 μM). Although VS1 has a moderate potency, we demonstrated that it specifically targets STARD3 in the cells and induces its degradation. Overall, the results confirm the reliability of the computational strategies herein applied and the identification of the first hit compound for the development of novel potent STARD3 inhibitors.
2019
Lapillo, M.; Salis, B.; Palazzolo, S.; Poli, G.; Granchi, C.; Minutolo, F.; Rotondo, R.; Caligiuri, I.; Canzonieri, V.; Tuccinardi, T.; Rizzolio, F....espandi
File in questo prodotto:
File Dimensione Formato  
2019_14.pdf

solo utenti autorizzati

Tipologia: Versione finale editoriale
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 5.07 MB
Formato Adobe PDF
5.07 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/997726
Citazioni
  • ???jsp.display-item.citation.pmc??? 9
  • Scopus 15
  • ???jsp.display-item.citation.isi??? 16
social impact