Nature Chemical Biology: using protein array to develop spindlin 1 small molecule inhibitor

Histone modification is one of the basic mechanisms of epigenetic regulation, which is considered to constitute a kind of "histone code", regulating the organization and interpretation of genetic information at chromatin level One mode of histone modification is to recruit a kind of effector called "reader", which regulates gene activity and chromatin structure by adjusting chromatin switch state, and then affects cell division, proliferation, differentiation and apoptosis It is worth noting that histone modification and its "reader" recognition are disordered in many diseases such as cancer In recent years, histone "reader" has gradually become an important target in drug development A famous example is the bromo domain of Brd4 There are many kinds of "reader" domains that can recognize histone modification, such as PhD zinc finger, Tudor, chromo, PWWP, MBT, bah, bromo, Yeats, etc they can recognize and decode "histone code" in a specific way of modification site and type Therefore, finding specific inhibitors for histone readers is a hot topic in the field of epigenetics Histone methylation is a kind of important histone modification, which mainly occurs on residues such as lysine and arginine It can be recognized and interpreted by aromatic pocket in reader In view of the structural similarity of aromatic cage pocket, the development of small molecular inhibitors targeting different methylation "readers" has become a challenge Scientists from the University of Texas M.D Anderson Cancer Center, the University of Italy's degli studi Di Salerno, and Tsinghua University's Center for advanced innovation in biology, Based on the construction of histone reader domain protein chip and the evolution of structure-activity relationship, a small molecule inhibitor for spindlin-1 was developed, which provides a new technical mode for drug screening and development targeting at the model domain in the future Researchers constructed a protein array chip of histone lysine methylation "reader" domain, which involves 98 protein domains belonging to Tudor, chromo, PhD, bah, MBT, PWWP, ank, agenet, heat and other types Then, a fluorescence based detection method was used to target the 98 potential "reader" targets with a small molecule inhibitor labeled with biotin "Lab on chip" high throughput evaluation and screening The potential targets of eml405, spindlin1, phf20, l3mbtl1, 53BP1, etc., were successfully selected by the research team using this technology and verified in vitro binding experiments Paper link: http://