TY - JOUR
T1 - 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
AU - Koval, Alexey
AU - Bassanini, Ivan
AU - Xu, Jiabin
AU - Tonelli, Michele
AU - Boido, Vito
AU - Sparatore, Fabio
AU - Amant, Frederic
AU - Annibali, Daniela
AU - Leucci, Eleonora
AU - Sparatore, Anna
AU - Katanaev, Vladimir L.
N1 - Funding Information: This work was supported by the Novartis Foundation for Medical-Biological Research , grant #17C153 to V.L.K.; J.X. was recipient of the Theodor et Gabriela Kummer PhD fellowship (University of Lausanne) Publisher Copyright: © 2021 The Author(s)
PY - 2021/10/15
Y1 - 2021/10/15
N2 - 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.
AB - 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.
KW - Clofazimine
KW - Medicinal chemistry
KW - Patient-derived xenograft
KW - Riminophenazine
KW - Triple-negative breast cancer
KW - Wnt signaling
UR - http://www.scopus.com/inward/record.url?scp=85108114632&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ejmech.2021.113562
DO - https://doi.org/10.1016/j.ejmech.2021.113562
M3 - Article
C2 - 34116325
SN - 0223-5234
VL - 222
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 113562
ER -