Non-covalent hydrophobic tags and protein degradation

An article that recently caught my eye set me thinking about the liabilities of hydrophobicity – where a ligand binds to a protein, leaving a lipophilic motif exposed to cytosol. Long et al in Chemistry and Biology 2012, 19, 629 (see also Neklesa and Crews, Nature 2012, 487, 308  discuss the role of lipophilic motifs binding non-covalently to proteins, which directs the protein to the proteasome for degradation. Specifically, the authors investigated the binding of (Boc)3Arg conjugated Trimethoprim to DHFR and the resultant reduction of DHFR levels in mammalian cells. The effect was blocked by Trimethoprim or by proteasome inhibitors. Ethacrynic acid, a covalent inhibitor of GST, also induced degradation of GST when tagged with Boc3Arg.

The main thrust of the articles is in the context of a therapeutic strategy, but arguably, in the case of off-target proteins, could unanticipated degradation due to “tagging” by a drug result in toxic events possibly only manifested over the long term, if the lipophilicity enhanced degradation is modest?

While the authors discuss ligands with a Boc3Arg motif, it is not a huge leap to think of, for example, drugs with lipophilic biaryl groups that become exposed, on binding of a polar head group, to an off-target protein, with consequent demolition by the proteasome.

If this is truly physiologically relevant, can the (unwanted) degradation phenomenon be reduced with a more uniform distribution of polarity in a drug molecule? Or, put another way, is it better to have a molecule of lipophilicity X with a reasonably uniform surface distribution of polarity, or a compound with the same lipophilicity but a non-uniform surface distribution of polarity? Intuitively I would prefer the former, but if anyone has seen any analysis of the distribution of polarity and developability, I would love to see it. Given that lipophilicity seems to be discussed as a global phenomenon for a molecule, perhaps considering local lipophilicity may be useful as well.

A couple of additional relevant articles related to covalent binding of a lipophilic tag and proteasome degradation are Neklesa et al Nature Chem. Biol., 2011, 7, 538 and H. S. Tae et al ChemBioChem 2012, 13, 538