Fragments vs PKC-ι: 7-azaindole strikes again

A common question in library design concerns novelty: should you populate your library with custom-made, hitherto unseen molecules, or just buy off-the shelf compounds? While the first strategy might make it easier to get patentable leads, the second approach is faster and has a long history of success. Indeed, simple 7-azaindole served as a starting fragment for three clinical compounds: vemurafenib, PLX3397, and AZD5363. A new paper in J. Med. Chem. by Alvin Hung and colleagues at A*STAR illustrates just how versatile this scaffold can be.

The researchers were interested in protein kinase C iota (PKC- ι), one of a family of 10 kinases that has been implicated in cancer. A high concentration screen of 1700 fragments yielded 15 hits with measurable IC₅₀ values, three of which were substituted 7-azaindoles. Compound 1, which has the highest ligand efficiency, was chosen to pursue.

Initial SAR quickly revealed that the bromine could be replaced with larger substituents, and a combinatorial library led to more potent molecules, such as compound 25. This was docked into a previously reported crystal structure of PKC- ι, which suggested the possibility of adding a positively charged moiety to interact with a couple aspartic acid residues. This strategy was successfully accomplished in compound 36, with low micromolar activity.

  

Adding a methoxy substituent to force a twist in the molecule led to an additional increase in potency, and rigidifying the amine led to compound 39, with mid-nanomolar activity. This was profiled against 101 kinases and found to be reasonably selective, though it did hit some other PKCs. The molecule was also not very permeable, and perhaps for this reason did now show good cellular activity.

To further optimize the series the researchers turned to group efficiency analysis, which revealed that the central benzimidazole element was the least efficient portion of the molecule. Earlier SAR and modeling had suggested that the unsubstituted nitrogen was making an important hydrogen bond to the protein, but “moving” the other nitrogen led to a more potent molecule. Further tweaking led to low nanomolar compound 49, which also had improved cellular activity.

Overall this is a nice example of advancing a generic, promiscuous fragment to a novel, potent, and selective lead – all without crystallographic support. Though further characterization of these molecules is not reported, the authors do mention optimization of a second series starting from a different fragment. Stay tuned!