Abstract

There is currently great interest in compounds that modulate epigenetics. With respect to some epigenetic targets, such as histone decacetylases (HDACs), many inhibitors have been successfully developed and are in clinical trials for a variety of indications. Similarly, bromodomains have been shown, somewhat unexpectedly by some, to be highly druggable. However, there is an elephant in the room, and that is the histone acetyltransferase (HAT) family, which is large but essentially “undrugged” and barely has any compounds that could be considered to be useful tools. Why is it so hard to find good tool compounds for these enzymes? Not so long ago we undertook HTS against a MYST HAT [1] and eventually discovered a genuine hit that we have recently just optimized to nanomolar levels of inhibition. However, we encountered many problems en route. In this talk we will discuss such issues and how these could help explain why there are so few, if any, useful tool compounds for these enzymes.

[1] Falk H, Connor T, Yang H, Loft KJ, Alcindor JL, Nikolakopoulos GE, Surjadi RN, Bentley JD, Hattarki MK, Dolezal O, Murphy JM, Monohan BJ, Peat TS, Thomas T, Baell JB, Parisot JP, Street IP. An efficient high-throughput screening method for MYST family acetyltransferases, a new class of epigenetic drug targets. J. Biomol. Screening 16 (2011) 1196-1205.