The discovery of a novel antimetastatic Bcl3 inhibitor

Soukupová, 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.; Brancale, Andrea

Abstract

The development of antimetastatic drugs is an urgent healthcare priority for patients with cancer, because metastasis is thought to account for around 90% of cancer deaths. Current antimetastatic treatment options are limited and often associated with poor long-term survival and systemic toxicities. Bcl3, a facilitator protein of the NF-κB 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 using a virtual drug design and screening approach against a computational model of the Bcl3-NF-kB1(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-NF-kB1 binding, tumor colony formation, and cancer cell migration in vitro; and tumor stasis and antimetastatic activity in vivo, while 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 intracellular targets, and confirm Bcl3 as a potential antimetastatic target.

• Journal Article Type: Article
• Acceptance Date: Feb 24, 2021
• Online Publication Date: Mar 1, 2021
• Publication Date: May 1, 2021
• Deposit Date: Oct 22, 2024
• Publicly Available Date: Oct 29, 2024
• Journal: Molecular Cancer Therapeutics
• Print ISSN: 1535-7163
• Electronic ISSN: 1538-8514
• Publisher: American Association for Cancer Research
• Peer Reviewed: Peer Reviewed
• Volume: 20
• Issue: 5
• Pages: 775-786
• DOI: https://doi.org/10.1158/1535-7163.mct-20-0283
• Public URL: https://uwe-repository.worktribe.com/output/13307554