By Rich Soll (Senior Advisor, Strategic Initiatives, WuXi AppTec (@richsollwx).

Richard Lerner is a visionary.  He and Sydney Brenner, both of the Scripps Research Institute (Scripps) first published on DNA-encoded libraries (DELs) in 1992 in the Proceedings of the National Academy of Sciences.  Yet it was only within the last few years has interest in DELs, a potentially disruptive technology, become “viral” in the life science industry.  Twenty-six years later, in December 2018 DELopen was announced as an open-access platform supported by WuXi AppTec to better enable academics and non-profit organizations to utilize DEL technology in drug discovery.

Lerner serves as the Scientific Advisory Board chairman for DELopen.  He is joined by other esteemed colleagues, Phil Baran (Scripps), Carolyn Bertozzi (Stanford), Raymond E. Dwek (Oxford), Martin Friedlander (Scripps), Michael Kaplitt (Weill Cornell Medical College), Roger Kornberg (Stanford), Casey Krusemark (Purdue), David R. Liu (Broad Institute, Harvard, MIT), Alan Saghatelian (Salk), Barry Sharpless (Scripps), Richard Soll (WuXi AppTec), and Chi-Huey Wong (Scripps).

The goal of the DELopen platform is to provide free access of DEL libraries owned by participating partners to academic and non-profit partners in drug discovery to aid in target validation, in identification of chemical matter via screening, in building structure activity relationships (SAR), and in hit elaboration. The new platform strives to provide full protection of intellectual properties for both user and technology provider, thus lowering the IP barrier and promoting in-depth collaboration. Ultimately, the industry/academia alliance will unlock the true potential of DEL technology for future drug discovery.

Recently, I had the opportunity to discuss with Lerner the opportunities with DELopen as the next generation DEL. “This is a game changer to worldwide drug discovery and is of transformative potential,” exclaimed Lerner. “It will unlock the true potential of DEL technology.”

“DEL is a technological platform linking genetics and small molecules that allows for the synthesis and screening on an unprecedented scale, wherein billions of molecules are generated and screened through a biophysical affinity assay,” explained Lerner. “Each molecule carries a unique, covalently linked chemical tag composed of DNA fragments (series of oligonucleotides). The DNA fragment-bound compounds which exhibit high affinity to an immobilized target are then released, the DNA code subjected to amplification, and then sequenced. Each sequence of DNA uniquely corresponds to a single molecule.” The “actives” are synthesized without DNA tags for re-confirmation and further characterization.

One of the purposes in screening these large libraries is to find hits against targets thought to be “intractable” by conventional methods, such as protein-protein interactions (PPIs) in addition to more traditional targets. The realization of the vision that DELs can efficiently yield candidates with favorable properties was first demonstrated with GSK2236294, an inhibitor of soluble epoxide hydrolase (sEH). This was followed by disclosures of the advancement of RIP1 kinase inhibitor GSK2982772 for inflammatory diseases and the disclosure of AZ3451, an allosteric ligand to the protease activated receptor 2 (PAR2).

Lerner recently reported on a late-stage modification toolbox approach to annotate complex organic compounds with amplifiable DNA barcodes. This can be easily incorporated into a DEL. Lerner explained, “basically what we did is invent a volatile linker that on one end has a 3-methyldiazarene, which you know if you shine a light on it will become a carbine that will insert into almost anything. On the other end, there is an azide, so we can use Sharpless chemistry to do a copper-catalyzed 1:3 dipolar addition to some alkyne. In this way, we use carbene chemistry to hook this linker and DNA onto almost anything.  So we label these complex mixtures and then we peform a selection on the insulin receptor and get a really interesting molecule. Would you believe, we have been able to identify a polycyclic Metformin analog where all the nitrogen atoms are in the same place they are in the bis-guanidine, which is metformin!  In the literature, this compound as found in nature, lowers triglycerides and blood glucose.”

Lerner continued, “similarly, we have recently reported in Angewandte Chemie a novel PARP1 inhibitor from the natural products-enriched DEL.” Lerner plans to turn his next attention to the opioid receptor, responding to the opioid crisis.

Since DNA is highly charged and soluble only in water, historically chemical synthesis of DELs was limited to aqueous medium, thus limiting chemistries of choice for DEL elaboration….or so we thought. But Lerner discussed two new pieces of chemistry which he has been following.

“Phil Baran and Phil Dawson of Scripps Research Institute recently have reported a strategy for biomolecule modification using an adaptation of reversible adsorption to solid support (RASS; inert quaternary ammonium support),” noted Lerner. “This allows for reactions to be run in organic solvents at near anhydrous conditions. Now, far more complex chemistry can be built into the libraries. It’s a neat trick.”

A second recent synthetic advancement comes from the Sharpless lab, specifically the use of thionyl tetrafluoride as a connective hub for bioconjugation to DNA and proteins. This reagent reacts with primary amines to form iminosulfur oxydifluoride (R-N=SOF2) which can react with primary amines to give sulfamides, while the reagent reacts with secondary amines to give sulfuramidimdoyl fluoride products. These species are modified further by nucleophiles. “I’ve never heard of anybody using a DNA-sparing electrophilic gas before this,” proclaimed Lerner. “It’s fundamentally a new brand of chemistry.”

Lerner continued, “with the support provided in this partnership we aim to bridge academia and industry and jointly promote the application of DEL technology in the field of new drug discovery. In fact, this can be traced back to an editorial that Sydney and I wrote in Angewandte Chemie, basically discussing the perennial conundrum in drug discovery – academic drug discovery worldwide. Namely, chemists have compounds but no targets, while biologists have targets but no compounds. What Sydney and I suggested in this editorial is that these libraries could be distributed to academia with no harm, since the libraries are encoded. But an additional benefit is that we can achieve chemical annotation of a given DEL, as it may be anticipated that an individual library may perform well against a particular target or target class. So can you imagine the change in the world of drug discovery when academics can see if their compounds perturb their system, like what we have done with the insulin receptor!”

Lerner concluded: “We all understand the importance of drug discovery, but what the key stakeholders, the patients, want are drugs.  I’d like to applaud WuXi for supporting the next generation academic drug discovery where we can interrogate biological systems and seek therapeutics simultaneously. And that’s what this extraordinary partnership is going to allow.”