A groundbreaking study conducted by the Dr. Marcus Conrad and his team at Helmholtz in Munich, revealed the discovery of a revolutionary anticancer drug known as icFSP1which increases the vulnerability of cancer cells to ferroptosis; the results of this research have been published in the prestigious journal Natures.
Ferroptosis is a cellular process characterized by iron-dependent oxidative degradation of cell membranes, counteracted by ferroptosis suppressor protein-1 (FSP1), a crucial factor in the regulation of ferroptosis. Despite the potential of FSP1 as a promising target for cancer therapy, the development of effective in vivo FSP1 inhibitors has been challenging.
To fill this gap, the research team looked meticulously about 10,000 small molecule compounds and identified icFSP1 as a highly potent and viable drug with in vivo efficacy.
Significantly, the team unveiled the mechanism of action behind icFSP1, which involves inducing phase separation of FSP1, a physical phenomenon within cells similar to the separation of oil and water and interestingly, icFSP1 showed strong inhibition of tumor growth in vivo and led to distinct FSP1 condensates within tumor tissue, presenting a novel concept to fight tumors by promoting FSP1 phase separation and facilitating ferroptosis.
Resistance to chemotherapy and metastasis are major clinical challenges in cancer treatment but surprisingly, during processes such as dedifferentiation or metabolic rewiring, some malignant tumor cells acquire an intrinsic vulnerability to ferroptosis, therefore targeting ferroptosis has emerged as a promising strategy for cancer therapy.
What are the results obtained in the study on icFSP1?
In 2019, Dr. Marcus Conrad’s team had previously identified the first specific inhibitor of FSP1, iFSP1.
“However, this compound is not suitable for in vivo use and exhibits off-target effects at high concentrations”
Conrad explained. To identify in vivo active ferroptosis inducers that specifically target FSP1, the team conducted a comprehensive screening campaign in cells, followed by rigorous validation studies in drug metabolism and pharmacokinetics (DMPK). These efforts led to the discovery of icFSP1, a novel class of compounds that sensitize numerous human cancer cells to ferroptosis and attenuate tumor growth in vivo.
Through extensive investigations into the mechanism of action of icFSP1, the team revealed that icFSP1 does not directly inhibit the activity of the FSP1 enzyme, but rather triggers subcellular relocalization of FSP1 through phase separation, distinguishing it from the mechanism of action of icFSP1. initial FSP1 inhibitor, iFSP1.
Toshitaka Nakamura, the lead author of the study, further clarified that “icFSP1-induced FSP1 condensations require distinct structural components and N-terminal myristoylation,” as demonstrated through experiments involving recombinant FSP1 proteins, various cell lines, and tumor samples.
Ferroptosis has garnered immense interest in multiple fields, including cancer, neurodegenerative diseases, and ischemia/reperfusion injury, and similarly, phase separation is a fundamental physical phenomenon underlying signal transduction and processes basic biologics associated with numerous diseases. This study represents the first ever connection between ferroptosis and phase separation.
“Our study will serve as a valuable model for the future development of innovative therapeutic approaches in diseases such as cancer, where ferroptosis/phase separation plays a crucial role”
Conrad explained, offering one promising prospect for future advances in this field.
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