ERX-41; Promising compound by targeting LIPA is a new Achilles heel therapeutic strategy for hard-to-treat solid tumors by induction of endoplasmic reticulum stress

Recently there has been an incredible shift in cancer treatment, from broad-spectrum cytotoxic drugs to targeted drugs known as small molecules and macromolecules. Although traditional therapies have been effective in cancer treatment, they often have adverse side effects due to their nonspecific action on both normal and tumor cells. The endoplasmic reticulum (ER), is known to control a variety of vital cellular processes, including protein production, folding/misfolding, and unfolding. The ER affects cell survival and death by activating the unfolded protein response (UPR) if the balance is not preserved. Dysregulation of these pathways' homeostasis in the ER is consequently linked to the emergence and development of cancer's pathological states. Therefore, targeting ER stress and ER stress-mediated apoptosis in cancer cells by small-molecule emerged as an intriguing unconventional approach that may be an effective strategy for treating cancers. This review attempts to introduce one of the newest small molecules known as ERX-41 for cancer has a poor clinical outcome strategy for solid tumors, including breast, brain, pancreatic and ovarian cancer. ERX-41 induces ER stress resulting in cell death through specific LIPA targeting. Importantly, demonstrated that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding and induce ER stress. This molecules targeted approach has a large therapeutic window, with no adverse effects either on normal cells and leading of new Achilles heel discovery in the therapeutics development for multiple hard-to-treat solid tumors.