B-cell lymphoma 3-encoded protein is a
protein that in humans is encoded by the BCL3gene.[5][6]
This gene is a proto-
oncogene candidate. It is identified by its translocation into the
immunoglobulin alpha-
locus in some cases of
B-cell leukemia. The protein encoded by this gene contains seven
ankyrin repeats, which are most closely related to those found in
I kappa B proteins. This protein functions as a transcriptional
coactivator that activates through its association with
NF-kappa B homodimers. The expression of this gene can be induced by NF-kappa B, which forms a part of the autoregulatory loop that controls the nuclear residence of
p50 NF-kappa B.[7]
The role of Bcl3 in
solid tumors was established through the ability of Bcl3 to promote
metastasis without affecting primary tumor growth or normal mammary function, within models of
ErbB2-positive
breast cancer.[18] Further research has uncovered the role of Bcl3 in promoting progression of other solid tumors. The role of Bcl3 in promoting tumor hallmarks has been most widely reported for advanced
colorectal cancer; where Bcl3 expression is up-regulated in >30% of colorectal cancer cases and is associated with a poor prognosis. For example, in colorectal cancer models, elevated Bcl3 expression was found to activate
AKT signalling,[19] drive a
cancer stem cell phenotype through enhancing
β-catenin signalling,[20] drive the
COX-2 mediated response to
inflammatory cytokines,[21] and protect colorectal tumor cells against
DNA damage.[22] The role of Bcl3 in enabling multiple cancer
hallmarks in colorectal carcinogenesis has been reviewed.[23]
Bcl3 also influences responses of cancer cells to treatment. Bcl3 promotes resistance to alkylating
chemotherapy in
gliomas,[27] DNA damaging agents in colorectal cancer,[22] and regulates the cancer
immune checkpoint control gene
PD-L1 in ovarian cancer cells.[28]
The first discovery of a small molecule anti-metastatic Bcl3 inhibitor was reported utilising a virtual
drug design and screening approach, targeting the
protein-protein interaction between Bcl3 and partner protein p50.[29] The
virtual screening hit compound showed potent intracellular Bcl3-inhibitory activity, and led to reductions in
NF-κB signalling, tumor colony formation and cancer cell migration within in vitrocellular models of
breast cancer. In vivo inhibition of tumor growth and anti-metastatic activity was observed in
invasive breast cancer models, without overt systemic
toxicity.
Development
TNA Therapeutics, is the only company engaged in developing a BCL3 inhibitor. TNAT-101, is an orally bioavailable, small molecule inhibitor of the novel target BCL3. BCL3 is a transcriptional regulator of multiple pathways critical for cancer initiation, maintenance and progression. It plays an important role in tumor growth, cell death, migration, metastasis and cancer stem cell viability.
Crossen PE, Kennedy MA, Heaton DC, Morrison MJ (September 1993). "Cloning and sequencing of a t(14;19) breakpoint that involves the C mu switch region". Genes, Chromosomes & Cancer. 8 (1): 60–62.
doi:
10.1002/gcc.2870080110.
PMID7691160.
S2CID85217954.
McKeithan TW, Ohno H, Dickstein J, Hume E (November 1994). "Genomic structure of the candidate proto-oncogene BCL3". Genomics. 24 (1): 120–126.
doi:
10.1006/geno.1994.1588.
PMID7896265.
Neumann M, Fries H, Scheicher C, Keikavoussi P, Kolb-Mäurer A, Bröcker E, et al. (January 2000). "Differential expression of Rel/NF-kappaB and octamer factors is a hallmark of the generation and maturation of dendritic cells". Blood. 95 (1): 277–285.
doi:
10.1182/blood.V95.1.277.
PMID10607713.
B-cell lymphoma 3-encoded protein is a
protein that in humans is encoded by the BCL3gene.[5][6]
This gene is a proto-
oncogene candidate. It is identified by its translocation into the
immunoglobulin alpha-
locus in some cases of
B-cell leukemia. The protein encoded by this gene contains seven
ankyrin repeats, which are most closely related to those found in
I kappa B proteins. This protein functions as a transcriptional
coactivator that activates through its association with
NF-kappa B homodimers. The expression of this gene can be induced by NF-kappa B, which forms a part of the autoregulatory loop that controls the nuclear residence of
p50 NF-kappa B.[7]
The role of Bcl3 in
solid tumors was established through the ability of Bcl3 to promote
metastasis without affecting primary tumor growth or normal mammary function, within models of
ErbB2-positive
breast cancer.[18] Further research has uncovered the role of Bcl3 in promoting progression of other solid tumors. The role of Bcl3 in promoting tumor hallmarks has been most widely reported for advanced
colorectal cancer; where Bcl3 expression is up-regulated in >30% of colorectal cancer cases and is associated with a poor prognosis. For example, in colorectal cancer models, elevated Bcl3 expression was found to activate
AKT signalling,[19] drive a
cancer stem cell phenotype through enhancing
β-catenin signalling,[20] drive the
COX-2 mediated response to
inflammatory cytokines,[21] and protect colorectal tumor cells against
DNA damage.[22] The role of Bcl3 in enabling multiple cancer
hallmarks in colorectal carcinogenesis has been reviewed.[23]
Bcl3 also influences responses of cancer cells to treatment. Bcl3 promotes resistance to alkylating
chemotherapy in
gliomas,[27] DNA damaging agents in colorectal cancer,[22] and regulates the cancer
immune checkpoint control gene
PD-L1 in ovarian cancer cells.[28]
The first discovery of a small molecule anti-metastatic Bcl3 inhibitor was reported utilising a virtual
drug design and screening approach, targeting the
protein-protein interaction between Bcl3 and partner protein p50.[29] The
virtual screening hit compound showed potent intracellular Bcl3-inhibitory activity, and led to reductions in
NF-κB signalling, tumor colony formation and cancer cell migration within in vitrocellular models of
breast cancer. In vivo inhibition of tumor growth and anti-metastatic activity was observed in
invasive breast cancer models, without overt systemic
toxicity.
Development
TNA Therapeutics, is the only company engaged in developing a BCL3 inhibitor. TNAT-101, is an orally bioavailable, small molecule inhibitor of the novel target BCL3. BCL3 is a transcriptional regulator of multiple pathways critical for cancer initiation, maintenance and progression. It plays an important role in tumor growth, cell death, migration, metastasis and cancer stem cell viability.
Crossen PE, Kennedy MA, Heaton DC, Morrison MJ (September 1993). "Cloning and sequencing of a t(14;19) breakpoint that involves the C mu switch region". Genes, Chromosomes & Cancer. 8 (1): 60–62.
doi:
10.1002/gcc.2870080110.
PMID7691160.
S2CID85217954.
McKeithan TW, Ohno H, Dickstein J, Hume E (November 1994). "Genomic structure of the candidate proto-oncogene BCL3". Genomics. 24 (1): 120–126.
doi:
10.1006/geno.1994.1588.
PMID7896265.
Neumann M, Fries H, Scheicher C, Keikavoussi P, Kolb-Mäurer A, Bröcker E, et al. (January 2000). "Differential expression of Rel/NF-kappaB and octamer factors is a hallmark of the generation and maturation of dendritic cells". Blood. 95 (1): 277–285.
doi:
10.1182/blood.V95.1.277.
PMID10607713.