YZL-51N functions as a selective inhibitor of SIRT7 by NAD+ competition to impede DNA damage repair

The NAD⁺-dependent deacetylase SIRT7 is a pivotal regulator of DNA damage response (DDR) and a promising drug target for developing Cancer therapeutics. However, limited progress has been made in SIRT7 modulator discovery. Here, we applied peptide-based deacetylase platforms for SIRT7 enzymatic evaluation and successfully identified a potent SIRT7 Inhibitor YZL-51N. We initially isolated bioactive YZL-51N from cockroach (Periplaneta americana) extracts and then developed the de novo synthesis of this compound. Further investigation revealed that YZL-51N impaired SIRT7 enzymatic activities through occupation of the NAD⁺ binding pocket. YZL-51N attenuated DNA damage repair induced by ionizing radiation (IR) in colorectal Cancer cells and exhibited a synergistic Anticancer effect when used in combination with etoposide. Overall, our study not only identified YZL-51N as a selective SIRT7 Inhibitor from insect resources, but also confirmed its potential use in combined chemo-radiotherapy by interfering in the DNA damage repair process.

Molecular biology experimental approach; Natural product biochemistry; Pharmacology; Small molecule.