In:
Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 20, No. 5 ( 2021-05-01), p. 775-786
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.
Type of Medium:
Online Resource
ISSN:
1535-7163
,
1538-8514
DOI:
10.1158/1535-7163.MCT-20-0283
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2021
detail.hit.zdb_id:
2062135-8
SSG:
12
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