The Power of DNA-Encoded Libraries for Covalent Inhibitor Discovery

Most of the pharmaceutical industry’s reported drug discovery projects involve reversible target modulators. However, covalent inhibitors — i.e., irreversible — have long been the focus of research efforts because of their potential to produce highly potent therapies, and they currently make up ~30% of the drug market.¹ Despite advantages like long duration of action, the development of covalent inhibitor drugs has been historically hindered by challenges like a lack of selectivity and interference with biological assays.² Advances in drug discovery technology, however, have changed the paradigm, opening new possibilities for the development of covalent inhibitors.³ 

X-Chem’s proprietary and industry-leading DNA-encoded library (DEL) technology has become the premier tool for drug discovery in this area. With our validated DEL screening platform added to their arsenal, our partners access a massive library of compounds. This powerful technology has enabled X-Chem to lead the industry in developing covalent inhibitors, creating exciting avenues for novel therapeutics. 

Covalent Inhibitors and DEL: A Match Made … by X-Chem 

Covalent drugs can be incredibly potent, which is why there is growing interest in this class, as demonstrated by recent sales numbers.³ To fully support the needs of our partners in this area, we developed a proprietary solution: DELvalent. This irreversible selection platform has been validated against difficult target classes like cysteine mutants, proteases, E3 ligases and even kinases. It comes complete with a massive library of electrophilic warhead-equipped compounds, including approximately 40 warheads and over 100 billion compounds.  

Our pioneering scientists designed DELvalent to be the leading covalent DEL hit discovery method. They succeeded. X-Chem synthesized the world’s first electrophilic DELs and invented the screening methods used to discover specific irreversible compounds. Our proprietary approach delivers numerous benefits to increase our partners’ odds of success: 

• Exponentially reduced background binders for optimized signal 
• Increased selectivity and biochemical efficiency 
• Optimized safety and efficacy  

Our novel covalent affinity selection method allows the assessment of selectivity and directly relates signal-to-background with warhead-driven promiscuity. This provides an unparalleled opportunity to discover novel, potent covalent inhibitors with high selectivity and desirable pharmacological properties. Plus, because we pioneered this area of drug development, our partners don’t just access the industry’s most extensive and diverse screening library; they also have the leading experts in covalent DEL screening committed to identifying high-quality starting points that accelerate their programs — a recipe for exponential progress.  

A Track Record of Novel Success 

With X-Chem’s groundbreaking DEL screening library for covalent hit identification, combined with our high-powered scientific team, we offer the industry’s only platform that enables naïve DEL screening for selective irreversible inhibitors. Our covalent DEL technology has demonstrated that acrylamide-containing libraries can be made and screened, leading to the discovery of the first known epoxide-based Bruton’s Tyrosine Kinase (BTK) inhibitor.⁴  

Our experts also demonstrated selectivity and potency, as well as covalent cysteine engagement, using a variety of techniques: 

• X-ray crystallography 
• Thermal transition shift assay 
• Reporter displacement assay 
• Intact protein complex mass spectrometry (MS)  

X-Chem’s expertise in covalent inhibition selection methods is unmatched, and our proprietary DEL technology is revolutionizing the field of drug discovery. With the only platform enabling naïve DEL screening for selective irreversible inhibitors and a massive library of electrophilic warhead-equipped compounds, we are consistently discovering better starting points for our partners’ drug development programs. 

The Fast Track to Exponential Covalent Discovery 

X-Chem’s pioneering work in covalent inhibitor drug discovery has positioned us at the forefront of this field. Our proprietary 100 billion compound-strong DEL screening library and team of expert scientists have enabled us to innovate methods for discovering highly specific irreversible compounds. Plus, with the integration of artificial intelligence via ArtemisAI, we have further enhanced our ability to deliver exceptional small molecule drug discovery services, delivering more hits, faster than ever before. 

The future of DEL covalent drug discovery shows extraordinary potential, as the combination of DEL technology, medicinal chemistry and AI continue to revolutionize the field. By staying at the forefront of these advancements, X-Chem is positioned to provide clients with the industry’s most effective solutions for developing selective and potent covalent inhibitors. X-Chem’s expertise and innovative platforms make us the ideal partner for covalent inhibitor research.  

Small Molecules Hold Exponential Possibilities.  
Reach out to learn how we can help bring your covalent project to fruition. 

References

1. Sutanto, F., et al. Covalent inhibitors: a rational approach to drug discovery. RSC Med. Chem., 2020,11, 876-884.
2. Cully, M. Novel chemistry for covalent inhibitors. Nature Reviews Drug Discovery, 2020, 19, 754.
3. Boike, L. et al. Advances in covalent drug discovery. Nature Reviews Drug Discovery, 2022, 21, 881-898.
4. Guilinger, J.P. et al. Novel irreversible covalent BTK inhibitors discovered using DNA-encoded chemistry. Bioorganic & Medicinal Chemistry, 2021, 42, 116223.

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