The discovery of a novel anti-metastatic Bcl3 inhibitor

Soukupova, Jitka, Bordoni, Cinzia, Turnham, Daniel J. ORCID: https://orcid.org/0000-0002-2540-7363, Yang, William W., Seaton, Gillian, Gruca, Aleksandra, French, Rhiannon, Lee, Kok Yung, Varnava, Athina, Piggott, Luke, Clarkson, Richard W. E. ORCID: https://orcid.org/0000-0001-7389-8673, Westwell, Andrew D. ORCID: https://orcid.org/0000-0002-5166-9236 and Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419 2021. The discovery of a novel anti-metastatic Bcl3 inhibitor. Molecular Cancer Therapeutics 10 (5) , pp. 775-786. 10.1158/1535-7163.MCT-20-0283

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Abstract

The development of anti-metastatic drugs is an urgent healthcare priority for cancer patients, since metastasis is thought to account for around 90% of cancer deaths. Current anti- metastatic treatment options are limited and often associated with poor long-term survival and systemic toxicities. Bcl3, a facilitator protein of the NF-kB family, is associated with poor prognosis in a range of tumor types. Bcl3 has been directly implicated in the metastasis of tumor cells, yet is well tolerated when constitutively deleted in murine models, making it a promising therapeutic target. Here we describe the identification and characterization of the first small molecule Bcl3 inhibitor, by employing a virtual drug design and screening approach against a computational model of the Bcl3-NFkB1(p50) protein-protein interaction. From selected virtual screening hits, one compound (JS6) showed potent intracellular Bcl3-inhibitory activity. JS6 treatment led to reductions in Bcl3-NFkB1 binding, tumor colony formation and cancer cell migration in vitro; and tumor-stasis and anti-metastatic activity in vivo, whilst being devoid of overt systemic toxicity. These results represent a successful application of in silico screening in the identification of protein-protein inhibitors for novel intra-cellular targets, and confirm Bcl3 as a potential anti-metastatic target.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Biosciences Research Institutes & Centres > European Cancer Stem Cell Research Institute (ECSCRI) Schools > Medicine Schools > Pharmacy
Publisher:	American Association for Cancer Research
ISSN:	1535-7163
Date of First Compliant Deposit:	5 March 2021
Date of Acceptance:	24 February 2021
Last Modified:	06 Nov 2024 13:30
URI:	https://orca.cardiff.ac.uk/id/eprint/139337

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