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Invest New Drugs. 2019 Feb 19. doi: 10.1007/s10637-019-00741-3. [Epub ahead of print]

GNS561, a new lysosomotropic small molecule, for the treatment of intrahepatic cholangiocarcinoma.

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Genoscience Pharma, 10 Rue d'Iéna, Marseille, France.
Genoscience Pharma, 10 Rue d'Iéna, Marseille, France.
Biomarker Discovery Department, Evotec SAS, 195 Route d'Espagne - BP13669, Toulouse, France.
Department of Oncology, Hôpital Paris Saint Joseph, 185 Rue Raymond Losserand, Paris, France.


Among the acquired modifications in cancer cells, changes in lysosomal phenotype and functions are well described, making lysosomes a potential target for novel therapies. Some weak base lipophilic drugs have a particular affinity towards lysosomes, taking benefits from lysosomal trapping to exert anticancer activity. Here, we have developed a new lysosomotropic small molecule, GNS561, and assessed its activity in multiple in vitro intrahepatic cholangiocarcinoma models (HuCCT1 and RBE cell lines and patient-derived cells) and in a chicken chorioallantoic membrane xenograft model. GNS561 significantly reduced cell viability in two intrahepatic cholangiocarcinoma cell lines (IC50 of 1.5 ± 0.2 μM in HuCCT1 and IC50 of 1.7 ± 0.1 μM in RBE cells) and induced apoptosis as measured by caspases activation. We confirmed that GNS561-mediated cell death was related to its lysosomotropic properties. GNS561 induced lysosomal dysregulation as proven by inhibition of late-stage autophagy and induction of a dose-dependent build-up of enlarged lysosomes. In patient-derived cells, GNS561 was more potent than cisplatin and gemcitabine in 2/5 and 1/5 of the patient-derived cells models, respectively. Moreover, in these models, GNS561 was potent in models with low sensitivity to gemcitabine. GNS561 was also efficient in vivo against a human intrahepatic cholangiocarcinoma cell line in a chicken chorioallantoic membrane xenograft model, with a good tolerance at doses high enough to induce an antitumor effect in this model. In summary, GNS561 is a new lysosomotropic agent, with an anticancer activity against intrahepatic cholangiocarcinoma. Further investigations are currently ongoing to fully elucidate its mechanism of action.


Anticancer; Apoptosis; Cholangiocarcinoma; GNS561; Lysosome


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