Despite its name, fat mass obesity-associated protein (FTO) is implicated not just in obesity but also cancer and neurological disorders. The DNA/RNA demethylase is an “epigenetic eraser” that removes methyl groups from nucleic acids, thereby regulating multiple genes. Several inhibitors have been reported, but many of these are weak and nonspecific. In a recent
J. Med. Chem. paper, Takayoshi Suzuki and collaborators at Kyoto Prefectural University of Medicine, Osaka University, and Kyoto University describe merging two of these to create a more potent molecule.
The researchers started with four known inhibitors, all of which had structures bound to FTO deposited in the Protein Data Bank. These structures were then used to merge HZ (below in red) with the other (sometimes
barely) fragment-sized molecules. For two approaches the resulting merged molecules were inactive, but when HZ was merged with MA (below in blue) the resulting molecule was active in a biochemical assay and showed high affinity as assessed by isothermal titration calorimetry (
ITC).
Modeling studies on compound 11b suggested why it might have better affinity than the starting molecules. Additional modeling also suggested why the other merged molecules were inactive.
Given its highly polar nature compound 11b was inactive in cells, but transforming the carboxylic acid into an ester produced a prodrug that caused cell death in a cancer cell line in which FTO is overexpressed. The prodrug also caused an increase in
N6-methyladenosine in mRNA and caused changes in transcription consistent with FTO inhibition. Although the potency is too low for a
chemical probe, and the molecule contains a number of chemical liabilities, this on-target activity is encouraging.
This paper exemplifies that fragment merging is not necessarily easy, and I give plaudits to the researchers for describing designs that did not work – too often papers only trumpet successes. Moreover, as the researchers acknowledge, even the successfully merged compound has a lower ligand efficiency than the parent compounds. This is another illustration of why it is important to start with the best fragments possible – not just in terms of various metrics but in terms of overall chemical attractiveness as well. It will be fun to see follow-up work.
