Fragment-based Hit Identification Of AF9 And ENL YEATS Domain

Epigenetic regulation includes histone post-translational modifications, such as methylation, ubiquitination, acetylation. These modifications are recognized by the corresponding "reader", such a recognization is associated with the gene activation.Recent studies have shown that the YEATS domain is considered as a reader to recognize the histone acetylation and other acylations. Among human YEATS domains, ENL and AF9 are more extensively studied. Studies pointed out that dysfunction of the YEATS domain was often associated with human diseases,especially the cancer. AF9 can recruit DOT1L, and then methylate H3K79. The DOTIL-mediated pathway is associated with the tumor metabolism. Experiments show that the ENL YEATS domain is associated with the proliferation of the cancer cell. For the background, we are committed to looking for potential small molecule inhibitors to occupy the YEATS domain pocket, so as to achieve the role of inhibition of the cancer cell growth. Fragment-based drug discovery is widely used in the field of drug screening with its simple compound structure, high hit rate and other unique advantages. We conducted a fragment-based screening experiment against the AF9 YEATS domain using the NMR method. Based on STD and WaterLOGSY experiments, 11 compounds were identified from the small molecule library, and two compounds were confirmed to bind the YEATS domain by the chemical shift perturbation experiment. One of the small molecules binds the AF9 YEATS domain with a high affinity of 9.7 ?M and binds the acetylated histone binding site of the YEATS domain. The small molecule also has an affinity of 31?M for the ENL YEATS domain. Furthermore, we predict the structure of the complex of the small molecule and the AF9 YEATS domain and carry on the structure analysis on the basis of the initial evolution of small molecules. As far as we know, it is the first small molecule inhibitor found by the YEATS domain protein, providing some insights into the subsequent structural development of small molecule inhibitors and the study of YEATS domains inhibitors.PSPH is a phosphatase that catalyzes the hydrolysis of L-phosphoserine,which is a rate-limiting step for the mammalian biosynthesis of L-serine. The study revealed that PSPH is a rate-limiting step in tumor metabolic abnormalities and therefore could serve as a potentially therapeutical target. The fragment-based screening experiment was also conducted for PSPH, and the structure of PSPH was analyzed.