Charting new chemical space for kinase inhibitors

Since the advent of imatinib, kinase inhibitors have become a thing in drug discovery, with more than two dozen already approved. Indeed, kinases are the targets of more than a third of reported fragment-derived compounds to reach the clinic. Given that all 500+ human kinases bind ATP, you would think that the chemical space would be pretty well picked over by now. As Hongtao Zhao and Amedeo Caflisch at the University of Zurich show in a recent Bioorg. Med. Chem. Lett. paper, this is not the case.

The researchers started by extracting all 26,668 kinase inhibitors with MW < 600 Da and IC₅₀ or Ki < 10 µM from the ChEMBL database; three quarters of these were better than 1 µM. These have been tested in aggregate against 367 kinases, of which 88 have more than 100 reported inhibitors!

The molecules were then deconstructed into 10,302 ring-containing fragments, such as benzene (7.1% of kinase inhibitors), 2-methylaminopyrimidine (3.5%) and N-methylmorpholine (2.3%), as well as more obscure structures. In fact, more than half (53%) of these fragments were not found within 7.5 million commercial compounds in the ZINC database. In other words, many fragments that form a part of known kinase inhibitors are not represented among commercial compounds, despite many vendors offering “kinase inhibitor libraries”.

What about the reverse question, analyzing commercial molecules for new kinase inhibitors? The researchers focused on possible “hinge-binding” fragments – those that have at least one hydrogen bond donor and one acceptor in close proximity to one another so as to be able to interact with a conserved region of kinases. Not surprisingly, more than half of the fragments (5681) found by deconstructing the kinase inhibitors fit this description. More interestingly, 196,904 potential hinge binders resulted from deconstructing the ZINC compounds, of which only 1% had been reported as kinase inhibitors.

Digging into the data more deeply, the researchers classified hinge binders as monocyclic, bicyclic, and multicyclic. This analysis revealed that the overlap between kinase inhibitors and commercial compounds was particularly low for multicyclic fragments. This intuitively makes sense: medicinal chemists often turn to ring construction to fix all manner of problems, both pharmaceutical and IP-related, so the under-representation in commercial compounds is likely because medicinal chemists introduce rings into simpler starting molecules. Also, from a molecular complexity standpoint, multicyclic ring systems may be less likely to bind to a wide variety of proteins than simpler monocyclic fragments.

More than five years ago Practical Fragments highlighted a paper from Abbott describing their efforts to generate novel hinge binders. As this and related analyses show, there is still plenty of chemical space left to explore and exploit.