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The discovery of a novel anti-metastatic Bcl3 inhibitor

Soukupova, Jitka, Bordoni, Cinzia, Turnham, Daniel J. ORCID:, Yang, William W., Seaton, Gillian, Gruca, Aleksandra, French, Rhiannon, Lee, Kok Yung, Varnava, Athina, Piggott, Luke, Clarkson, Richard W. E. ORCID:, Westwell, Andrew D. ORCID: and Brancale, Andrea ORCID: 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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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: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
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: 10 Dec 2023 16:54

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