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An optimised Bcl-3 inhibitor for melanoma treatment

Saamarthy, Karunakar LU ; Daams, Renée LU ; Sime, Wondossen LU ; Persson, Cecilia ; Chygorin, Eduard ; Ahlqvist, Kristofer LU ; Evans-Axelsson, Susan LU orcid ; Strand, Daniel LU and Massoumi, Ramin LU (2025) In British Journal of Pharmacology 182(11). p.2426-2446
Abstract

Background and Purpose: Malignant melanoma is the most lethal form of skin cancer, characterised by a poor survival rate. One of the key factors driving the aggressive growth of melanoma cells is the elevated expression of the proto-oncogene Bcl-3. This study aims to optimise, evaluate and characterise a second-generation Bcl-3 inhibitor, using melanoma as a model to demonstrate its potential therapeutic efficacy. Experimental Approach: We synthesised and screened a series of structural analogues and selected A27, the most promising candidate for further investigation. We assessed whether A27 disrupted the interaction between Bcl-3 and its binding partner, p50, and examined the subsequent effects on cyclin D1 expression. Additionally,... (More)

Background and Purpose: Malignant melanoma is the most lethal form of skin cancer, characterised by a poor survival rate. One of the key factors driving the aggressive growth of melanoma cells is the elevated expression of the proto-oncogene Bcl-3. This study aims to optimise, evaluate and characterise a second-generation Bcl-3 inhibitor, using melanoma as a model to demonstrate its potential therapeutic efficacy. Experimental Approach: We synthesised and screened a series of structural analogues and selected A27, the most promising candidate for further investigation. We assessed whether A27 disrupted the interaction between Bcl-3 and its binding partner, p50, and examined the subsequent effects on cyclin D1 expression. Additionally, we evaluated the impact of A27 on melanoma cell proliferation and migration in vitro, as well as its therapeutic efficacy in various in vivo melanoma models. Key Results: Nuclear magnetic resonance (NMR) confirmed that A27 directly binds to Bcl-3, effectively inhibiting its function. By disrupting the Bcl-3/p50 interaction, A27 led to a significant down-regulation of cyclin D1 expression. In cellular assays, A27 markedly reduced proliferation and migration of melanoma cells. In vivo, treatment with A27 resulted in a substantial reduction in melanoma tumour growth, with no observed toxicity in treated animals. Conclusions and Implications: At present, no other Bcl-3 inhibitors exist for clinical application in the field of oncology, and as a result, our novel findings provide a unique opportunity to develop a highly specific drug against malignant melanoma to meet an urgent clinical need.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Bcl-3, cell proliferation, cyclin D1, melanoma, metastasis
in
British Journal of Pharmacology
volume
182
issue
11
pages
21 pages
publisher
Wiley
external identifiers
  • pmid:39943627
  • scopus:85218840676
ISSN
0007-1188
DOI
10.1111/bph.17467
language
English
LU publication?
yes
id
2d3ba0f0-c087-4579-bd43-6e32f3c70c2d
date added to LUP
2025-07-01 11:19:16
date last changed
2025-07-02 03:16:09
@article{2d3ba0f0-c087-4579-bd43-6e32f3c70c2d,
  abstract     = {{<p>Background and Purpose: Malignant melanoma is the most lethal form of skin cancer, characterised by a poor survival rate. One of the key factors driving the aggressive growth of melanoma cells is the elevated expression of the proto-oncogene Bcl-3. This study aims to optimise, evaluate and characterise a second-generation Bcl-3 inhibitor, using melanoma as a model to demonstrate its potential therapeutic efficacy. Experimental Approach: We synthesised and screened a series of structural analogues and selected A27, the most promising candidate for further investigation. We assessed whether A27 disrupted the interaction between Bcl-3 and its binding partner, p50, and examined the subsequent effects on cyclin D1 expression. Additionally, we evaluated the impact of A27 on melanoma cell proliferation and migration in vitro, as well as its therapeutic efficacy in various in vivo melanoma models. Key Results: Nuclear magnetic resonance (NMR) confirmed that A27 directly binds to Bcl-3, effectively inhibiting its function. By disrupting the Bcl-3/p50 interaction, A27 led to a significant down-regulation of cyclin D1 expression. In cellular assays, A27 markedly reduced proliferation and migration of melanoma cells. In vivo, treatment with A27 resulted in a substantial reduction in melanoma tumour growth, with no observed toxicity in treated animals. Conclusions and Implications: At present, no other Bcl-3 inhibitors exist for clinical application in the field of oncology, and as a result, our novel findings provide a unique opportunity to develop a highly specific drug against malignant melanoma to meet an urgent clinical need.</p>}},
  author       = {{Saamarthy, Karunakar and Daams, Renée and Sime, Wondossen and Persson, Cecilia and Chygorin, Eduard and Ahlqvist, Kristofer and Evans-Axelsson, Susan and Strand, Daniel and Massoumi, Ramin}},
  issn         = {{0007-1188}},
  keywords     = {{Bcl-3; cell proliferation; cyclin D1; melanoma; metastasis}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{2426--2446}},
  publisher    = {{Wiley}},
  series       = {{British Journal of Pharmacology}},
  title        = {{An optimised Bcl-3 inhibitor for melanoma treatment}},
  url          = {{http://dx.doi.org/10.1111/bph.17467}},
  doi          = {{10.1111/bph.17467}},
  volume       = {{182}},
  year         = {{2025}},
}