Four of the six approved fragment-derived drugs are kinase inhibitors, and three of these bind in the active site. Despite these successes, there are plenty of opportunities for new kinase-directed drugs, particularly those targeting cancer resistance mutations. In a recent Brief Bioinform. article, Guang-Fu Yang and colleagues at Central China Normal University describe a new tool to facilitate these discoveries.
The researchers started by trawling multiple databases such as kinase.com, DrugBank, ChEMBL, and the Protein Data Bank for kinase inhibitors. The results were combined and collated to yield a set of 7783 kinase-inhibitor fragment complexes, with more than 3000 unique fragments. Most of these bind in the “front cleft” of the active site, where the adenine of ATP normally binds, but several hundred also sit in the so-called back pocket or the intervening area.
What’s nice is that all this information is available on a free website called KinaFrag. You can download the structures yourself, but the site can also be browsed or searched. Fragments are annotated with links to various databases; here’s an example.
There are some bugs. While I was able to search by physicochemical parameters such as molecular weight and number of hydrogen bond donors, I could not get the substructure search to work. I’d be curious as to whether readers could do so.
To demonstrate the utility of KinaFrag, the researchers describe a case study in which they started with the anticancer drug larotrectinib, which inhibits TRK family kinases. However, the molecule is less effective against several mutations observed in the clinic. Examining the bound structure revealed that the mutations introduce steric clashes. Retaining the hinge-binding fragment while performing virtual screening of fragments from KinaFrag led to molecules such as YT3, potent against both wild type TRKA and two resistance mutants, and further optimization resulted in YT9.
Not only was YT9 active against the wild type and mutant forms of TRKA, it showed good oral bioavailability and pharmacokinetics in rats. Encouragingly, the molecule slowed tumor growth in both wild type and mutant TRKA mouse xenograft models.
One could debate whether this is an example of FBLD; the discovery of YT9 could also be considered a classic case of scaffold hopping. But semantics aside, this is a nice example of thinking in terms of fragmenting molecules. More broadly, KinaFrag looks like a useful tool for work on kinases – especially if the substructure search works.