Category: Drug Target Strategies

1009-E - A Discovery Platform for Selective MYST Lysine Acetyltransferase Inhibitors

Wednesday, February 7, 2018
11:30 AM - 12:30 PM

The acetylation of histones by lysine acetyltransferases (KATs) is essential for normal transcriptional regulation of gene expression. The MYST family of KATs (KAT5-8) includes MOZ (Monocytic Leukemia Zinc Finger, KAT6A), which has been reported to drive oncogenic transcriptional programs in haematological malignancies. On this basis, MOZ is an attractive target for therapeutic intervention. However, to date no member of the MYST family has been successfully targeted with drug-like small molecules.

We have conducted HTS campaigns to identify small molecule inhibitors of members of the MYST family using a high-throughput, homogenous assay format measuring the acetylation of synthetic substrates. We identified inhibitors from several chemical classes and secondary assays were used to eliminate assay-interfering compounds and prioritise the hits. Medicinal chemistry optimisation elaborated a series selective for MOZ, and reversibility of binding was confirmed by surface plasmon resonance. X-ray crystallography also demonstrated that the inhibitor molecules bind in the AcetylCoA binding pocket.  Finally, treatment of fibroblast cells with MOZ inhibitors induces cellular senescence, which phenocopies the genetic loss of MOZ.

Our results suggest that the MYST family proteins are targetable with drug-like small molecule inhibitors and potentially form a novel class of anticancer drugs acting via epigenetic regulation of transcription.

Hendrik Falk

Senior Research Fellow
CancerTherapeutics CRC
Parkville, Victoria, Australia

Dr Hendrik Falk is working with the CancerTherapeutics CRC (CTx) as Director Discovery Technology at the Walter+Eliza Hall Institute.
Hendrik was awarded a B.A. in Business Information Technology and studied pharmacy at the Martin-Luther Universität Halle/ Germany, receiving the licence to practise in 2000. During his doctoral thesis at the Freie Universität Berlin, Dr Falk examined the involvement of G proteins in cellular signalling. During post-doctoral studies in the Molecular Tumour Genetics group at the Max-Delbrück-Center, Berlin/ Germany, Dr Falk expanded his skills to the high-throughput screening.
At CTx he is responsible for design and development of high throughput screens and follow-up studies. His contributions further include design & development of the CTx eResearch platform.