Metal-binding fragments vs glutaminyl cyclases

Metal-binding fragments have a long history in FBLD; the first mention on Practical Fragments was back in 2010. The idea is to use the strong interaction between a fragment and a protein-bound metal as an affinity anchor for further optimization. The latest example, by Jie-Young Song, Soosung Kang and collaborators at Korea Institute of Radiological & Medical Sciences, Ewha Womans University, and elsewhere was published in ACS Med. Chem. Lett.

 

Glutaminyl cyclases such as glutaminyl-peptide cyclotransferase (QC) and glutaminyl-peptide cyclotransferase-like protein (isoQC) convert N-terminal glutamine or glutamate residues on proteins to pyroglutamates. This modification tends to stabilize proteins, and it has been implicated in several diseases. In particular, modification of CD47 by isoQC seems to be important for the ability of cancer cells to evade the immune system.

 

QC and isoQC are closely related enzymes with a zinc-containing active site. Capitalizing on this, the researchers tested a library of 36 potential metal-binding fragments in a functional assay against QC. Most of the compounds tested were inactive, though 11 had IC₅₀ values less than 0.8 mM. A few of these, including compound ab, were used to generate a second library of just half a dozen larger fragments, and compound 9 turned out to quite potent.

 

The researchers recognized that compound 9 has two potential zinc-binding moieties, and docking suggested the newly added amino-thiadiazole was likely responsible for the increased activity. Structure-based design ultimately led to compound 22b, with low nanomolar activity against QC and isoQC. The molecule did not seem to be generally cytotoxic, but it did increase phagocytosis of cancer cells in vitro, consistent with an effect on the “don’t eat me” function of CD47.

 

Unfortunately, no information is provided on the selectivity of compound 22b against other zinc-dependent enzymes. Moreover, unlike an earlier example of starting with metallophilic fragments, no ADME data are provided. But whether or not this particular series advances, it is nice to see metallophilic fragments being explored.