DNA‐Encoded Compound Libraries as Open Source: A Powerful Pathway to New Drugs

Abstract

“… We envisioned an iterative system where a unique DNA tag identifier that encoded the event was appended to each newly formed molecule. These vast collections of molecules are known today as DNA- encoded chemical libraries (DECLs), and allow scientists to do selections on the benchtop that previously required access to large and complex high-throughput screening centers …” Read more in the Guest Editorial by Richard A. Lerner and Sydney Brenner. At about the same time that libraries of biological molecules were enjoying success, chemists began to construct vast libraries of organic molecules by using methods such as “split and pool” synthesis in a field that became known as combinatorial chemistry. The problem, however, was that although these libraries could be very large, they were not easily deconvoluted for determining the nature of the active molecules. Thus, it is one thing to build large libraries of molecules that can be used to bind to targets, but its quite another matter to identify the active molecules. A library of large size is useful for covering chemical space, but in chemistry large size is the enemy of identification! In 1992, we were, of course, mindful of advances in libraries of biological molecules and were thinking about how synthetic small molecules in organic libraries could be made to enjoy some of the advantages of biological molecules. It occurred to us that if we could link the diversity of chemical synthesis to the power of genetics we could obviate some of the problems with combinatorial libraries of organic molecules. Thus, we envisioned an iterative system where a unique DNA tag identifier that encoded the event was appended to the newly formed molecule for each step in the chemical synthesis. In the end, one had a vast collection of molecules where each one carried a unique DNA tag that encoded its synthetic history. This was the first time in organic chemistry where organic molecules carried information beyond their intrinsic structures. It was of special importance that the molecules in the library contained information capable of replication so that it could be retrieved when only a few molecules are present. While we referred to these libraries as “encoded combinatorial libraries today they are most often referred to as DNA-encoded chemical libraries (DECLs). Much has happened since our initial studies. The requirement for orthogonal and compatible chemistries has been greatly simplified by the use of enzymes to construct the DNA tag. Major advances in next-generation DNA sequencing and information technology have allowed scientists to identify hits from even the largest libraries. But the most important advance is that methods to construct diverse DNA-tagged organic compounds in the library in a way that does not disrupt the DNA continue to emerge from the synthetic organic community. If inventing new DNA-compatible reactions continues to capture the attention of chemists, there is little doubt that the nature and diversity of the libraries will continue to improve. In these enhanced libraries, we expect that the efficiency of drug discovery will scale with library size. With these advances in hand, the DECL field has exploded with the requisite participation of academic laboratories as well as biotechnology and pharmaceutical companies. Recently, the Fifth International Symposium on DNA-Encoded Chemical Libraries was held at the ETH Zurich, where one could access the state of the field. First, virtually every major pharmaceutical company and biotechnology company was present, thus giving witness to the fact that DNA-encoded chemical libraries have arrived as a key component of the armamentarium of drug discovery. Many useful hits for important targets were described and some of the discovered molecules have already entered the clinic. Much time was spent comparing high-throughput screening (HTS) to the DECL approach both in the presentations and informal discussions. There are, of cour