Indatraline

From the steady stream of drug repurposing patent applications published under the Patent Cooperation Treaty (PCT), we have selected fifteen documents that first became available during the first quarter of 2025. As in each installment, some of these claims are truly surprising. Few researchers would have expected that SSRI antidepressants such as sertraline and indatraline could exhibit pronounced anticancer effects. Equally unexpected is the disclosure that sitagliptin, the first antidiabetic agent from the DPP-4 inhibitor class, may be used for the treatment of glioblastoma. Another striking example is the report that artemisinin derivatives, well known for their use against malaria, may induce differentiation in undifferentiated erythroid and myeloid cells in patients with myelodysplastic syndrome. In addition, the compound bucillamine—relatively obscure in Western medicine but long used for the treatment of rheumatoid arthritis in East Asia—has been proposed for potential benefit in organophosphate poisoning. These highlights exemplify the breadth of innovation currently shaping the drug repurposing landscape. The reviewed patent applications originate from a diverse range of jurisdictions, including France, Spain, Greece, Slovenia, South Korea, China, Japan, Canada, and the United States, illustrating the global nature of ongoing research efforts in this field.

Cholesterol serves as a vital lipid that regulates numerous physiological processes. Nonetheless, its role in regulating cell death processes remains incompletely understood. In this study, we investigated the role of cholesterol trafficking in immunogenic cell death. Through cell-based drug screening, we identified two antidepressants, sertraline and indatraline, as potent inducers of the nuclear translocation of TFEB (transcription factor EB). Activation of TFEB was mediated through the autophagy-independent lipidation of MAP1LC3/LC3 (microtubule associated protein 1 light chain 3). Both compounds promoted cholesterol accumulation within lysosomes, resulting in lysosomal membrane permeabilization, disruption of autophagy and cell death that could be reversed by cholesterol depletion. Molecular docking analysis indicated that sertraline and indatraline have the potential to inhibit cholesterol binding to the lysosomal cholesterol transporters, NPC1 (NPC intracellular cholesterol transporter 1) and NPC2. This inhibitory effect might be further enhanced by the upregulation of NPC1 and NPC2 expression by TFEB. Both antidepressants also upregulated PLA2G15 (phospholipase A2 group XV), an enzyme that elevates lysosomal cholesterol. In cancer cells, sertraline and indatraline elicited immunogenic cell death, converting dying cells into prophylactic vaccines that were able to confer protection against tumor growth in mice. In a therapeutic setting, a single dose of each compound was sufficient to significantly reduce the outgrowth of established tumors in a T-cell-dependent manner. These results identify sertraline and indatraline as immunostimulatory agents for cancer treatment. More generally, this research shed light on novel therapeutic avenues harnessing lysosomal cholesterol transport to regulate immunogenic cell death.Abbreviation: ATG5: autophagy related 5; ATG13: autophagy related 13; DKO: double knockout; ICD: immunogenic cell death; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; LGALS3: galectin 3; LDL: low-density lipoprotein; LMP: lysosomal membrane permeabilization; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTX: mitoxantrone; NPC1: NPC intracellular cholesterol transporter 1; NPC2: NPC intracellular cholesterol transporter 2; TFE3: transcription factor E3; TFEB: transcription factor EB; ULK1: unc-51 like autophagy activating kinase 1.