Triple-negative breast cancer (TNBC) is a cancer subtype critically dependent upon excessive activation of Wnt pathway. The anti-mycobacterial drug clofazimine is an efficient inhibitor of canonical Wnt signaling in TNBC, reducing tumor cell proliferation in vitro and in animal models. These properties make clofazimine a candidate to become first targeted therapy against TNBC. In this work, we optimized the clofazimine structure to enhance its water solubility and potency as a Wnt inhibitor. After extensive structure-activity relationships investigations, the riminophenazine 5-(4-(chlorophenyl)-3-((2-(piperazin-1-yl)ethyl)imino)-N-(pyridin-3-yl)-3,5-dihydrophenazin-2-amine (MU17) was identified as the new lead compound for the riminophenazine-based targeted therapy against TNBC and Wnt-dependent cancers. Compared to clofazimine, the water-soluble MU17 displayed a 7-fold improved potency against Wnt signaling in TNBC cells resulting in on-target suppression of tumor growth in a patient-derived mouse model of TNBC. Moreover, allowing the administration of reduced yet effective dosages, MU17 displayed no adverse effects, most notably no clofazimine-related skin coloration.
Optimization of the clofazimine structure leads to a highly water-soluble C3-aminopyridinyl riminophenazine endowed with improved anti-Wnt and anti-cancer activity in vitro and in vivo / A. Koval, I. Bassanini, J. Xu, M. Tonelli, V. Boido, F. Sparatore, F. Amant, D. Annibali, E. Leucci, A. Sparatore, V.L. Katanaev. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 222(2021 Oct 15), pp. 113562.1-113562.15.
|Titolo:||Optimization of the clofazimine structure leads to a highly water-soluble C3-aminopyridinyl riminophenazine endowed with improved anti-Wnt and anti-cancer activity in vitro and in vivo|
BASSANINI, IVAN (Co-primo) [Investigation]
SPARATORE, ANNA CONCETTINA [Supervision] (Corresponding)
|Parole Chiave:||clofazimine; medicinal chemistry; patient-derived xenograft; riminophenazine; triple-negative breast cancer; Wnt signalingp|
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
|Data di pubblicazione:||15-ott-2021|
|Data ahead of print / Data di stampa:||30-mag-2021|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.ejmech.2021.113562|
|Appare nelle tipologie:||01 - Articolo su periodico|