In his Wednesday afternoon presentation, Tao Guo shared information about WuXi AppTec’s global open platform to support drug discovery. He focused on three aspects of the platform: targeted protein degraders (TPDs), targeted covalent inhibitors, and nucleic-acid therapeutics.
TPDs are receiving increased attention. Guo noted the use of E3 ligases and protein binders to leverage proteasome clearance mechanisms and thereby degrade target proteins. Two mechanisms are to use proteolysis-targeting chimera (PROTAC) technology and to apply molecular “glues.” As of today, some 20 compounds are in clinical trials, many of which have advanced to phase 2 studies. In addition to PROTACs, other TPD approaches include using the lysosomal pathway to help degrade targeted proteins. Because those compounds are advancing quickly, many new bifunctional molecules are entering clinical trials.
Guo summarized advantages and challenges of working with PROTAC TPDs. They can target otherwise nondruggable molecules. But PROTACs also are hard to design, currently requiring an empirical approach to synthesis and testing. They also are hard to make. The target protein binder, the linker, and the E3 ligase binder must be assembled sequentially. The resulting drug molecules are large and generally more lipophilic, presenting a purification challenge. Optimization is difficult because as with the design, it is an empirical process.
Guo next spoke about use of TPDs in his company’s covalent inhibitor platform. This is not only a process of binding to the binding pocket of the target protein, but its formal reaction then forms a covalent bond with the target protein. That makes the binding irreversible.
The FDA has approved many types of covalent inhibitors with different reactive groups and different target protein covalent bonds. To optimize covalent inhibitors, you optimize the warhead using reaction kinetics to improve selectivity. This technology also presents challenges. For example, such drug molecules are hard to design, requiring empirical design synthesis and testing. Synthesis is challenging because of the reactivity of the covalent compounds — a reaction mixture can be complex. And purification needs to be timely, using special methods that will not destroy the covalent compounds. Finally, optimizing the warhead’s selectivity also is an empirical process, requiring many rounds of synthesis and test cycles.
Guo’s third topic was nucleic-acid therapeutics. Not only are they in increasing demand, but a number of modalities are available for targeting nucleic acids including antisense, from small-interfering RNA (siRNA), single-guide RNA (sgRNA) for gene therapy, and messenger RNA (mRNA) for vaccines. There are many ways to target RNA chemically.
He described siRNA as an “information drug,” for which the sequence and topology are critically important. Following design of the molecule and sequence, the siRNA must be stabilized. And for delivery, you often need to conjugate it to a targeted warhead to deliver it to the right organ. He compared antisense with siRNA, which basically uses different mechanisms to degrade target RNA, but with similar goals.
Targeted delivery of RNA requires use of lipid nanoparticles. Lipid nanoparticles are composed of four units: steroids (often cholesterol), helpers (anionic phospholipids); polymers (usually polyethylene glycol based polymers), and cationic lipids.
Once again, Guo noted challenges of developing nucleic-acid therapeutics. The RNA/oligonucleotide component requires stabilization chemistry and design modifications that also must be approached empirically. Conjugation often is needed. For example, for targeted delivery to the liver, you need to conjugate siRNA with N-acetylgalactosamine (GalNAc) and also need lipid nanoparticles, all of which require synthesis and testing.
Guo pointed out that with his company’s open platform it can make monomers and nucleic-acid oligos and perform the conjugations. It can make lipid nanoparticles and assemble the components. As of now, the company has delivered some 20,000 oligos sequences and about 2,000 variations of lipid nanoparticles. The goal is to help accelerate discovery of nucleic-acid therapeutics.
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