Hit to lead discovery of the benzoylsulfonohydrazide WM-8014 as a potent inhibitor of the histone acetyltransferase KAT6A

David Leaver (Presenter)

Research output: Other contribution to conferencePresentation onlypeer-review

Abstract

Histone acetyltransferases (HATs) acetylate histones by using AcCoA and play key roles in epigenetic pathways. The lysine acetyltransferase KAT6A is a member of the MYST protein family, which is the largest family of HATs. KAT6A is the target of recurrent chromosomal translocations that can cause acute myeloid leukemia. Finding potent inhibitors of KAT6A might facilitate the discovery of novel drugs that could be used to treat certain types of cancer. A high-throughput screen for KAT6A inhibitors led to the discovery of the benzoylnaphthalene-2-sulfonohydrazide CTX-0124143 as a moderate inhibitor of KAT6A (IC50 = 1.0 uM). Exploration of the structure-activity relationships (SAR) and sequential medicinal chem. optimization facilitated the discovery of WM-8014 as a potent inhibitor of KAT6A (IC50 = 0.008 uM). X-ray crystallog. and surface plasmon resonance anal. showed that WM-8014 is a reversible AcCoA competitor. By inhibiting the activity of KAT6A, WM-8014 was observed to induce cellular senescence without showing signs of general toxicity.
Original languageEnglish
Publication statusPublished - 2019
Externally publishedYes
EventAmerican Chemical Society (ACS) Southwest-Rocky Mountain Regional Meeting - El Paso, United States
Duration: 13 Nov 201916 Nov 2019
https://www.acs.org/content/acs/en/meetings/regional/southwest-rockymountain.html

Conference

ConferenceAmerican Chemical Society (ACS) Southwest-Rocky Mountain Regional Meeting
Country/TerritoryUnited States
CityEl Paso
Period13/11/1916/11/19
Internet address

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