Screening for Inhibitors of the Chromatin Reader SGF29

PROJECT SUMMARY AML is a devastating disease with survival rates of only 30-35 percent and cure-rates have plateaued in recent years. The large mutational diversity of AML has frustrated efforts aimed at identifying precisely targeted therapies that may benefit a large proportion of patients with distinct molecular alterations. There is therefore an urgent, clinically unmet need to identify therapies targeting a common molecular pathway triggered by multiple leukemia-associated mutations in AML. Such therapies that target molecular pathways commonly dysregulated in a majority of AML may therefore benefit a large proportion of AML patients. Oncogenic transcription factors (TFs) such as MYC, homeobox (HOX) proteins and MEIS1 are aberrantly activated in AML. Since these TFs typically lack naturally evolved ligand-binding domains or enzymatic activity they have proven exceptionally difficult targets for drug discovery. However, epigenetic regulators such as chromatin readers often possess druggable features and can be targeted as an indirect means to suppress the tumorigenic activity of dysregulated TFs. Using a suite of orthogonal approaches, we have identified the chromatin reader SGF29 as a potent and highly selective regulator of transcription of AML oncogenes. SGF29 inhibition blocks leukemogenesis of diverse AML subtypes, and studies from other groups have pointed to the tumor-promoting roles of SGF29 in other cancers. This project will implement assays we have developed for use in large scale high-throughput screens (HTSs) to identify chemical compounds that inhibit SGF29. Such compounds will serve as chemical probes and provide novel starting points for drug discovery. Pilot screens of compounds from the LOPAC and ChemBridge libraries confirmed robustness of the primary screens. We have also developed highly selective secondary and tertiary assays that robustly recapitulate SGF29 activity in cellulo. These complementary assays will be used to rule out assay artifacts as well as insufficiently potent or non-selective compounds. Ultimately, compounds with significant SGF29-inhibitory activity will be tested to determine whether they can effectively impair leukemogenesis using established assays in mouse and human AML cell lines and patient samples, and to determine whether they impair normal hematopoietic cells. These novel compound classes that regulate SGF29 activity may lead to an entirely novel class of anti-AML therapeutics and further stimulate basic and applied research.