Virtual screening, SAR and discovery of 5-(indole-3-yl)-2-[(2-nitrophenyl)amino] [1,3,4]-oxadiazole as a novel Bcl-2 inhibitor

Ziedan, Noha I, Hamdy, Rania, Cavaliere, Alessandra, Kourti, Malamati, Prencipe, Filippo, Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419, Jones, Arwyn T ORCID: https://orcid.org/0000-0003-2781-8905 and Westwell, Andrew ORCID: https://orcid.org/0000-0002-5166-9236 2017. Virtual screening, SAR and discovery of 5-(indole-3-yl)-2-[(2-nitrophenyl)amino] [1,3,4]-oxadiazole as a novel Bcl-2 inhibitor. Chemical Biology and Drug Design 10.1111/cbdd.12936

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Abstract

A new series of oxadiazoles were designed to act as inhibitors of the anti-apoptotic Bcl-2 protein. Virtual screening led to the discovery of new hits that interact with Bcl-2 at the BH3 binding pocket. Further study of the structure-activity relationship of the most active compound of the first series, compound 1, led to the discovery of a novel oxadiazole analogue, compound 16j, that was a more potent small molecule inhibitor of Bcl-2. 16j had good in vitro inhibitory activity with sub-micromolar IC50 values in a metastatic human breast cancer cell line (MDA-MB-231) and a human cervical cancer cell line (HeLa). The antitumour effect of 16j is concomitant with its ability to bind to Bcl-2 protein as shown by an enzyme linked immunosorbent assay (IC50 = 4.27 μM). Compound 16j has a great potential to develop into highly active anticancer agent.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Pharmacy
Subjects:	R Medicine > RS Pharmacy and materia medica
Publisher:	Wiley-Blackwell
ISSN:	1747-0277
Date of First Compliant Deposit:	23 January 2017
Date of Acceptance:	19 December 2016
Last Modified:	08 Jan 2024 16:36
URI:	https://orca.cardiff.ac.uk/id/eprint/97648

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