%0 Journal Article
%T YZL-51N functions as a selective inhibitor of SIRT7 by NAD+ competition to impede DNA damage repair.
%A Kang TS
%A Yan YM
%A Tian Y
%A Zhang J
%A Zhang M
%A Shu Y
%A Huang J
%A He J
%A Tao CT
%A Zhu Q
%A Gu J
%A Lu X
%A Cheng YX
%A Zhu WG
%J iScience
%V 27
%N 6
%D 2024 Jun 21
%M 38947512
%F 6.107
%R 10.1016/j.isci.2024.110014
%X 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.