The discovery of a novel anti-metastatic Bcl3 inhibitor

Soukupova, Jitka, Bordoni, Cinzia, Turnham, Daniel J., Yang, William W., Seaton, Gillian, Gruca, Aleksandra, French, Rhiannon, Lee, Kok Yung, Varnava, Athina, Piggott, Luke, Clarkson, Richard W. E., Westwell, Andrew D. and Brancale, Andrea 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:	Biosciences Medicine 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:	13 May 2022 05:04
URI:	https://orca.cardiff.ac.uk/id/eprint/139337

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