Fragments vs KAT6A: ligand efficiency in action

Epigenetic writers such as histone acetyltransferases (HATs) control gene expression, which often goes awry in cancer. The gene encoding the lysine acetyltransferase KAT6A, for example, is amplified in multiple types of cancer, and its overexpression is associated with poor clinical outcomes for patients with ER⁺ breast cancer. A recent paper in Bioorg. Med. Chem. Lett. from Andrew Buesking and colleagues at Prelude Therapeutics reports a new series of inhibitors.

 

The researchers started by considering previously reported molecules such as PF-9363. Recognizing the importance of the central sulfonamide, they generated a library of 150 fragments containing this core and screened them in a biochemical assay. Taking a similar approach as other researchers reporting on a different epigenetic target we discussed last year, the Prelude team explicitly used ligand efficiency to call hits, setting the cutoff at > 0.3 kcal per mol per heavy atom.

 

A direct deconstruction of PF-9363 led to compound 6, but, seeking something novel, the researchers were drawn to compound 8, with similar ligand efficiency. Modifications were made to both of the terminal aromatic groups, leading to compound 13, which was co-crystallized with KAT6A. This led to further structure-guided modifications, with compound 25 being the most potent.

 

Unfortunately, further improvements in potency were not forthcoming, and the ligand efficiency had dropped steadily from both the initial fragment as well as PF-9363. The researchers conclude by stating that they “decided to pursue alternative approaches.” Still, this paper is a nice, concise example of using metrics both for pursuing a chemical series and, ultimately, discontinuing it.