Oligo-benzamide-based peptide mimicking tools for modulating biology.

The oligo-benzamide scaffold is a rigid organic framework that can hold 2-3 functional groups as O-alkyl substituents on its benzamide units, mirroring their natural arrangement in an α-helix. Oligo-benzamides demonstrated outstanding α-helix mimicry and can be readily synthesized by following high yielding and iterative reaction steps in both solution-phase and solid-phase. A number of oligo-benzamides have been designed to emulate α-helical peptide segments in biologically active proteins and showed strong protein binding, in turn effectively disrupting protein-protein interactions in vitro and in vivo. In this chapter, the design of oligo-benzamides for mimicking α-helices, efficient synthetic routes for producing them, and their biomedical studies showing remarkable potency in inhibiting protein functions are discussed.

Novel LIPA-Targeted Therapy for Treating Ovarian Cancer.

Ovarian cancer (OCa) is the most lethal form of gynecologic cancer, and the tumor heterogeneities at the molecular, cellular, and tissue levels fuel tumor resistance to standard therapies and pose a substantial clinical challenge. Here, we tested the hypothesis that the heightened basal endoplasmic reticulum stress (ERS) observed in OCa represents an exploitable vulnerability and may overcome tumor heterogeneity. Our recent studies identified LIPA as a novel target to induce ERS in cancer cells using the small molecule ERX-41. However, the role of LIPA and theutility of ERX-41 to treat OCa remain unknown. Expression analysis using the TNMplot web tool, TCGA data sets, and immunohistochemistry analysis using a tumor tissue array showed that LIPA is highly expressed in OCa tissues, compared to normal tissues. ERX-41 treatment significantly reduced the cell viability and colony formation ability and promoted the apoptosis of OCa cells. Mechanistic studies revealed a robust and consistent induction of ERS markers, including CHOP, elF2α, PERK, and ATF4, upon ERX-41 treatment. In xenograft and PDX studies, ERX-41 treatment resulted in a significant reduction in tumor growth. Collectively, our results suggest that ERX-41 is a novel therapeutic agent that targets the LIPA with a unique mechanism of ERS induction, which could be exploited to treat heterogeneity in OCa.