Evolution of ComInnex’s Building Blocks for DNA-encoded libraries (DELs)

 

What is common in life on Earth as we know it and the drug discovery industry we are working in? I guess you could say many things, but the answer I am looking for lies in the beautifully complex nature of DNA molecules. Changes in their structure led to the evolution of species over time, and now the very same biological unit is revolutionizing early phase drug discovery all over again, though in a totally different way. Rather than applying structural modifications to the biopolymer strands, this time, scientists are using bits of them as barcodes to label the next generation of drug molecules. First proposed in 1992, the DEL approach was to provide an alternative solution to high-throughput screening (HTS), which tend to be quite laborious and expensive, not to mention the low success rate they were sometimes showing.1 Reaching back to the principles of combinatorial chemistry and teaming up with molecular biology this novel technology quickly showed to overcome many problems making it possible to create, store and screen billions of compounds in just one simple vial.

Why am I bringing this up on our blog? Well, the reason is simple. ComInnex is being quite active in this area from the synthetic chemistry point of view. Namely, we are designing and synthesizing chemical building blocks (BBs) that later on our partners can make to react with each other or connect to DNA bits in line of creating libraries containing a vast amount of labeled drug-likes. And as life and drug discovery are constantly evolving through time we are also developing new and novel compounds to be tested and used.

Our selection started not long ago with bifunctional amino acids, which had the amine group protected (e.g. Fmoc, Boc, esters) and a variety of R-groups hanging from the scaffold. This, in the next round, we have developed further to BBs containing groups of carboxylic acids, amines, alkynes, heteroaryl halides as well as phenolic -OH, and we now have 100s of validated units.

The decorating motifs in use are not only known to facilitate the somewhat limited chemistry that is compatible with the attached DNA tags,2 but also are present in the toolkit of any trained synthetic organic chemist. To provide possibilities for building up branched structures at the end of the road, not only we have mono- and bi-functional BBs now, but we have extended our portfolio with tri-functional ones as well. Furthermore, following the trend and the significant interest showed in molecules with lower aromaticity we have added a little twist into our process of design & synthesis. We have integrated a selective hydrogenation step in our multi-step synthesis routes. This partial reduction, that often we do by the means of flow chemistry, results in molecules with high fsp3 character, which in turn provides better Absorption, Distribution, Metabolism, Excretion and Toxicity properties (e.g. increased solubility) and adds significantly to improved CYP and hERG profiles as well.3

One of the major obstacles scientists need to eliminate in order for DELs to be considered not only as a complementary technology to HTS, but rather as a replacement of it, is related to the compatibility of the applied chemistry with the DNA strands. The basic building blocks need to be designed in such a way that makes relatively easy to “connect” them to each other without destroying the hosting structure. This linkage might happen via utilizing novel synthetic approaches, such as using DNA not just an encoding agent, but also as a template to facilitate reactions between the individually attached building blocks.4 What’s so special about this idea, for me anyway, is that it looks so simple yet it has already given significant boosts to several therapeutics interests, including the emerging area of using drug-like macrocycles to modulate protein-protein interactions (PPIs).5

If you want to figure out if our Building Blocks are good for your chemistry, or even better, you want to be part of their evolution, get in touch with us quickly! Or you can just check back in from time to time to see the developments.

 

References:

1 Brenner, S. & Lerner, R. A. Proc. Natl. Acad. Sci. USA 89, 5381-5383 (1992)

2 Franzini, R. M. & Randolph, C. J. Med. Chem. 59, 6629–6644 (2016)

3 Ritchie, T. J. & Macdonald, S. J. F. Drug Discov. Today 14, 1011-1020 (2009)

4 Tse, B. N., Snyder, T. M., Shen, Y. & Liu, D. R. J. Am. Chem. Soc. 130, 15611-15626 (2008)

5 Connors, W. H., Hale, S. P. & Terrett, N. K. Curr. Opin. Chem. Bio. 26, 42-47 (2015)