The Discovery of a Novel Antimetastatic Bcl3 Inhibitor

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 antimetastatic treatment options are limited and often associated with poor long-term survival and systemic toxicities. Bcl3, a facilitator protein of the NF-B 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.

Loss of BCL-3 sensitises colorectal cancer cells to DNA damage, revealing a role for BCL-3 in double strand break repair by homologous recombination

“…Adjuvant treatment with novel chemical inhibitors of BCL-3 (66) may allow patients with higher BCL-3 expression to be sensitised to conventional radiotherapy, improving therapeutic response. As demonstrated in vivo , this finding would also be relevant to DNA damaging chemotherapy.…”

Multifaceted roles for BCL3 in cancer: a proto-oncogene comes of age

“…4 Transcription responses to BCL3 suppression predict alterations to the tumour microenvironment. BCL3 simultaneously promotes and represses different BCL3-responsive genes in a cell-context manner, as illustrated by the co-regulation of a subset of BCL3-responsive gene changes following BCL3 targeted siRNA in the breast cancer cell line MDA-MB-231 (left panel; adapted from [ 111 ]). These transcriptional signatures predict changes to the tumour microenvironment, for example that might impact on tumour surveillance, supported by independent observations on the effect of BCL3 on checkpoint-control (right panel [ 84 , 127 ];).…”

“…Pharmacological suppression of BCL3 in adult mice however led to a significant reduction in tumour volume in two xenograft models of breast cancer. This was accompanied by significant increases in cleaved caspase 3-positive cells but no significant difference in phospho-histone H3 within the tumours, suggesting that the primary effect of targeting BCL3 in breast tumours was an increase in apoptosis rather than a reduction in cell proliferation [ 111 ]. Similarly, enforced suppression of BCL3 by shRNA in DU145 prostate cancer xenografts resulted in a significant reduction in tumour growth which correlated with an increase in the number of cleaved caspase-3 positive cells within the treated tumours but no change in mitotic index [ 85 ].…”

“…The induction of IL8 by BCL3 in ovarian cancer cells [ 125 ] highlights one presumptive mechanism of BCL3-cytokine driven immune evasion in solid tumours via the recruitment of tumour-associated neutrophils [ 128 ]. Moreover, in describing a novel BCL3 inhibitor with anti-cancer properties in models of breast cancer [ 111 ], we have reported on the transcriptional responses of a panel of key NFkB-responsive genes to BCL3 inhibition mediated both by siRNA and pharmacologically. These genes included a number of cytokines that have critical roles in the recruitment and activation of immune cells within the tumour microenvironment (Fig.…”

Nasopharyngeal Carcinoma and Its Microenvironment: Past, Current, and Future Perspectives

“…It is reported that the NF-κB complex p50/p50/Bcl3 is prevalent in NPC but seldom found in a normal cell. Thus, Bcl3 inhibitors may represent promising therapeutic agents against NPC ( 202 , 207 ). Other than that, the route of administration and dosage of NF-κB inhibitors should consider their bioavailability and safety.…”