Practical Fragments recently discussed using fluorinated fragments for 19F NMR, but there are other halogens out there – are these useful for constructing fragment libraries? SGX Pharmaceuticals had a collection of fragments enriched with bromine atoms, the thought being that this atom would facilitate crystallography. Halogens can also make productive interactions with proteins, including so-called “halogen bonds” to backbone carbonyl atoms or pi-systems. With this in mind, Andreas Joerger at Cambridge University and Frank Boeckler at Eberhard-Karls University and their colleagues have assembled and screened a “halogen-enriched fragment library.” Their results are reported in a recent issue of J. Am. Chem. Soc.
The library consists of 79 non-reactive, soluble aromatic compounds containing bromine or iodine. Because these elements are so large, the researchers used a modified rule of 3 – instead of a molecular weight limit of 300, they limited the fragments to no more than 22 heavy atoms (see also our recent post on this topic here). They then screened this library against the Y220C mutant form of p53, which contains a surface crevice that destabilizes the protein and contributes to cancer cell survival. Thermal shift assays were used as the primary screen, with hits being confirmed by 2D NMR and ITC. This resulted in the discovery of compound 3, which crystallography confirmed was making a halogen bond to a backbone carbonyl.
Modifying the amine substituent improved potency modestly, and building off the phenyl ring towards a nearby pocket improved the potency further, albeit at a cost in ligand efficiency. Still, this compound (PhiKan5196) does represent the most potent Y220C binder reported, and represents an order of magnitude improvement over previous work. Moreover, the molecule induces apoptosis in p53 Y220C containing human cancer cell lines but not in matched wild-type p53 cell lines. (Unfortunately the compound also appears to be generally cytotoxic.)
This library is an interesting approach in part because it is somewhat heretical: for various reasons most library designers exclude molecules containing bromine or, especially, iodine. That said, the thyroid hormones do contain iodine aplenty, and MEK kinase seems to have a predilection for bromine or iodine as well. What do you think? Are halogenated fragments a useful tool for certain targets, or an unproductive diversion?