Blog | December 18, 2024

2024: A Year of Scientific Excellence for X‑Chem

By Matt Clark, Chief Scientific Officer

One of the best parts of being part of X-Chem is seeing all the great science being conducted around the company every day. Our clients know that we always do our utmost to solve their problems and create scientific value. But little of that work is ever shared with the outside world. This fact is not unique to X-Chem; the entire biopharma industry is slow to publish their research, for the obvious reasons that it can help enable competitors and erode competitive advantage. Fortunately, when you’ve been around as long as X-Chem has, just enough material trickles into the public domain to give the community a glimpse of our scientific developments.

In that light, 2024 has been a breakthrough year for X-Chem’s innovations. We had 12 peer-reviewed publications this year, and additional posters and conference talks around the world. These disclosures underscore the collaborative potential of our drug discovery approaches.

Pushing the boundaries of medicinal and synthetic chemistry 

Our team has advanced synthetic chemistry methodologies in several key areas. We reported novel approaches including deuteration through flow chemistry, amination of heterocycles using desaturative catalysis, and synthesis of novel amino acid building blocks via Negishi coupling. Our goals remain consistent: expanding the chemists’ toolkits to create compounds with potential bioactivity to improve human health.

As part of this broader effort, we are also closely following emerging trends in the field of covalent drug discovery, which has become increasingly important in targeting challenging proteins. We conducted a patent landscape analysis that focused on selective covalent reacting groups used in FDA-approved drugs. The analysis identified over 700 patent applications from more than 300 organizations, revealing strong interest in targeting key proteins like BTK, EGFR, KRAS G12C, and SARS-CoV-2 M^pro. This surge in innovation around targeted covalent inhibitors aligns with X-Chem’s own efforts to develop covalent modulators using our technology platform. As covalent drug discovery continues to evolve, we are excited to contribute our expertise to this rapidly developing field, helping to push the boundaries of what is possible in drug discovery.  

Leadership in the DNA-Encoded Library (DEL) space 

A cornerstone of our research has been DEL screening, which we’ve shown through diverse collaborative projects. One example was our work with Texas A&M, from which the hits directly from DEL screen demonstrated in vivo efficacy in a mouse model for tuberculosis. In another significant collaboration with AstraZeneca, we developed a novel approach based on the cyanoacrylamide motif for discovering reversible covalent inhibitors of the oncology target Bfl-1.

Our contributions to the scientific community through Perspectives highlights X-Chem’s thought leadership in the evolving field of DEL and its growing role in drug discovery. One of these Perspectives delves into the application of DEL in covalent ligand discovery, a field that has advanced significantly since we first reported on covalent DEL at the DEL symposium in 2015. Another Perspective, written in collaboration with AstraZeneca, examines the structural biology of DEL hits reported in the literature. This paper demonstrates that DEL screening tends to yield hits with novel binding modes and unexpected interactions with targets, in most cases resulting in exquisite selectivity. We often talk about the chemical diversity of DELs with respect to other libraries, but this paper shows that the true measure of chemical diversity is the wide range of biological diversity that can be found in the library. We see so many unprecedented interactions from DEL because we are surveying so much unprecedented chemical space.

Beyond hit identification 

Our work goes beyond hit identification, with several examples illustrating the progression from optimizing DEL hits into lead- and candidate-quality chemical matter. With Symeres, we described the discovery and optimization of macrocycles targeting the oncology target Mcl-1. While large and peptidic, these compounds showed acceptable permeability in addition to high potency, presumably aided by the observed transannular hydrogen bonding.

Similarly, our work with Abbvie on IL-17 inhibitors showed the power of DEL-generated data to provide structural insights. Aided by the DEL-data generated SAR and co-crystal structural information, the Abbvie team executed a very impressive medicinal chemistry campaign to arrive at a compound with good PK properties and potent efficacy in an animal model.

One of the most impactful projects was our collaboration with Arbutus on the development of inhibitors for SARS-CoV-2 M^pro. In a field where nirmatrelvir, a covalent M^pro inhibitor, was the first approved therapy, we identified a novel noncovalent inhibitor from DEL screening. The challenge with current Mpro inhibitors is that they often have limited efficacy against nirmatrelvir-resistant variants and may not offer broad-spectrum activity against emerging coronavirus strains, which poses a significant risk in future outbreaks. In our approach, we first used DEL screening to identify a promising noncovalent Mpro inhibitor with a distinct binding mode compared to nirmatrelvir. Our chemists further enhanced this lead by employing a macrocyclization strategy to lock the active conformation, leading to a remarkable 10-fold potency improvement.  

Computationally driven, partner-focused discovery

In addition to target-specific generation of chemical matter, we explored ligand generation for a broad target class in collaboration with Structural Genomics Consortium (SGC), Google, and Relay Therapeutics. By conducting large-scale multiplexed DEL selection followed by machine learning (ML) model training, active compounds were identified from commercial sources for 7 out of 16 screened targets, all of which were previously unliganded! This paper provides yet another proof point that high-quality DEL data is critical to drive the success of ML in drug discovery.

X-Chem helps partners advance by producing key discoveries that they can build upon. In a recent publication, our SGC colleagues used a DCAF1 ligand that we had identified through DEL screening to generate a functional PROTAC and fully characterize the structure of its ternary complex. This is the first example of a DEL-derived E3 binder supporting targeted protein degradation. And notably, DCAF1 was previously unliganded until our discovery in 2023.

To sum up, the state of scientific excellence at X-Chem is strong. Our approach to discovery is deeply rooted in collaboration. Our ultimate vision is to help create a healthier world by enabling others to achieve groundbreaking innovations. By continually enhancing capabilities in areas such as computational chemistry, DMPK, and data sciences, we are well-positioned to support our partners and clients in advancing their drug discovery efforts. Here’s to a great 2024, and even greater achievements with our partners in 2025!

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