An Efficient High-Throughput Screening Method for MYST Family Acetyltransferases, a New Class of Epigenetic Drug Targets

Falk, H; Connor, T; Yang, H; Loft, KJ; Alcindor, JL; Nikolakopoulos, G; Surjadi, RN; Bentley, JD; Hattarki, MK; Dolezal, O; Murphy, JM; Monahan, BJ; Peat, TS; Thomas, T; Baell, JB; Parisot, JP; Street, IP

Author(s): Falk, H; Connor, T; Yang, H; Loft, KJ; Alcindor, JL; Nikolakopoulos, G; Surjadi, RN; Bentley, JD; Hattarki, MK; Dolezal, O; Murphy, JM; Monahan, BJ; Peat, TS; Thomas, T; Baell, JB; Parisot, JP; Street, IP;
Details: Publication Year 2011-12,Volume 16,Issue #10,Page 1196-1205
Journal Title: JOURNAL OF BIOMOLECULAR SCREENING
Publication Type: Journal Article
Abstract: Epigenetic aberrations are increasingly regarded as key factors in cancer progression. Recently, deregulation of histone acetyltransferases (HATs) has been linked to several types of cancer. Monocytic leukemia zinc finger protein (MOZ) is a member of the MYST family of HAT s, which regulate gene expression in cell proliferation and differentiation. Deregulation of these processes through constitutively active MOZ fusion proteins gives rise to the formation of leukemic stem cells, rendering MOZ an excellent target for treating myeloid leukemia. The authors implemented a hit discovery campaign to identify small-molecule inhibitors of MOZ-HAT activity. They developed a robust, homogeneous assay measuring the acetylation of synthetic histone peptides. In a primary screening campaign testing 243 000 lead-like compounds, they identified inhibitors from several chemical classes. Secondary assays were used to eliminate assay-interfering compounds and prioritize confirmed hits. This study establishes a new high-throughput assay for HAT activity and could provide the foundation for the development of a new class of drugs for the treatment of leukemias. (Journal of Biomolecular Screening 2011:1196-1205)
Publisher: SAGE PUBLICATIONS INC
Keywords: LEUKEMIA ZINC-FINGER; HISTONE ACETYLTRANSFERASE; STEM-CELLS; CLINICAL-APPLICATIONS; GENE-EXPRESSION; FUSION PROTEIN; TRANSCRIPTION; CANCER; INHIBITOR; P300
Publisher's Version: https://doi.org/10.1177/1087057111421631
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2011-12-01 12:00:00