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Triple-negative breast cancer (TNBC) poses significant challenges due to its aggressive nature and limited treatment options. In this study, we investigated the impact of urea-based compounds on TNBC cells to uncover their mechanisms of action and therapeutic potential. Notably, polypharmacology urea analogues were found to work via p53-related pathways, and their cytotoxic effects were amplified by the modulation of oxidative phosphorylation pathways in the mitochondria of cancer cells. Specifically, compound 1 demonstrated an uncoupling effect on adenosine triphosphate (ATP) synthesis, leading to a time- and concentration-dependent shift toward glycolysis-based ATP production in MDA-MB-231 cells. At the same time, no significant changes in ATP synthesis were observed in noncancerous MCF10A cells. Moreover, the unique combination of mitochondrial- and p53-related effects leads to a higher cytotoxicity of urea analogues in cancer cells. Notably, the majority of tested clinical agents, but sorafenib, showed significantly higher toxicity in MCF10A cells. To test our hypothesis of sensitizing cancer cells to the treatment via modulation of mitochondrial health, we explored the combinatorial effects of urea-based analogues with established chemotherapeutic agents commonly used in TNBC treatment. Synergistic effects were evident in most tested combinations in TNBC cell lines, while noncancerous MCF10A cells exhibited higher resistance to these combination treatments. The combination of compound 1 with SN38 displayed nearly 60-fold selectivity toward TNBC cells over MCF10A cells. Encouragingly, combinations involving compound 1 restored the sensitivity of TNBC cells to cisplatin. In conclusion, our study provides valuable insights into the mechanisms of action of urea-based compounds in TNBC cells. The observed induction of mitochondrial membrane depolarization, inhibition of superoxide dismutase activity, disruption of ATP synthesis, and cell-line-specific responses contribute to their cytotoxic effects. Additionally, we demonstrated the synergistic potential of compound 1 to enhance the efficacy of existing TNBC treatments. However, the therapeutic potential and underlying molecular mechanisms of urea-based analogues in TNBC cell lines require further exploration., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

The neuronal ceroid lipofuscinoses (NCLs) are a family of rare lysosomal storage disorders. The most common form of NCL occurs in children harboring a mutation in the CLN3 gene. This form is lethal with no existing cure or treatment beyond symptomatic relief. The pathophysiology of CLN3 disease is complex and poorly understood, with current in vivo and in vitro models failing to identify pharmacological targets for therapeutic intervention. This study reports the characterization of the first CLN3 patient-specific induced pluripotent stem cell (iPSC)-derived model of the blood-brain barrier and establishes the suitability of an iPSC-derived neuron model of the disease to facilitate compound screening. Upon differentiation, hallmarks of CLN3 disease are apparent, including lipofuscin and subunit c of mitochondrial ATP synthase accumulation, mitochondrial dysfunction, and attenuated Bcl-2 expression. The model led to the identification of small molecules that cleared subunit c accumulation by mTOR-independent modulation of autophagy, conferred protective effects through induction of Bcl-2 and rescued mitochondrial dysfunction., Competing Interests: The authors declare the following competing financial interest(s): N.K. and P.C.T. are inventors on a patent application (PCT Int. App. WO 2019014547) submitted by Texas Tech University that covers the composition of matter of the compounds described herein.