By Matt Clark, CSO, X-Chem

As 2025 concludes, the momentum at X-Chem is evident. While our most impactful work is often shielded by intellectual property, this year’s high-profile publications and platform launches offers a window into how we are bridging the gap between massive data and clinical reality.

The launch of chemomics

The defining achievement of 2025 was the debut of our Chemomics platform. This represents the distillation of years of expertise in data analysis, structure-based descriptors, and DEL informatics into a tangible advantage for our partners. For our clients, Chemomics enables us to expand hit lists, execute scaffold-hops, and fully elaborate SAR landscapes in a matter of weeks rather than months. Seeing our partners immediately adopt this technology to compress their Hit-to-Lead timelines and sharpen their medicinal chemistry focus has been a highlight.

A leading role in mapping the proteome

The engine behind Chemomics is the unmatched scale and quality of our DEL data. We are seeing a global shift in how DEL data is used—not just for individual hits, but for mapping protein-ligand interactions across the unexplored proteome. X-Chem is proud to be a key driver of this movement through our involvement in the Target 2035 initiative. By contributing our high-quality data and expertise to this ambitious global mission to solve probe generation across the proteome, we are helping build the foundational infrastructure for the next decade of ML-driven discovery.

Enabling breakthroughs: the “push-start” for partner programs

Our partnership mission is often to provide the critical chemical “seed” that allows therapeutic programs to accelerate toward the clinic. We are fortunate that this year, several key successes have entered the public domain, allowing us to disclose the following milestones:

• Clinical momentum in oncology: A successful hit identification campaign provided a high-quality starting point for MOMA to optimize to MOMA-341, now a clinical candidate in phase 1 trials.
• Immunology advancements: We saw the reporting of significant progress in a major IL-17 program (Janssen), built upon a robust foundation identified through our DEL platform. This journey from hit to advanced lead demonstrates the power of our libraries in tackling high-value cytokine targets.
• Targeted protein degradation: Recent disclosures highlighted the discovery of novel ligands for the E3 ligase STUB1 (AstraZeneca) and the chromatin regulator WDR5 (SGC). These projects demonstrate the exquisite selectivity our libraries offer for modern chemical probes and E3 binders.

Toolbox to engineer next-generation leads

Our chemistry teams continue to pioneer methodologies that overcome the synthetic hurdles inherent in modern drug design. For instance, our disclosure of a photoredox-mediated amidine functionalization method offers a distinct advantage to “fine-tune” a molecule’s properties, helping our partners improve both the potency and the drug-like characteristics of their compounds.

In addition, in collaboration with Pfizer, we developed stereoselective routes for trans-cyclopropyl ester synthesis. These new synthetic routes allow our partners to execute rapid scale-up while maintaining precise control over molecular geometry, ensuring the transition from initial discovery to large-scale production is as smooth as possible.

While we take pride in our scientific disclosures, our ultimate focus is unchanged: applying the most advanced drug discovery platform in the world to create molecules that improve lives. Every project we prosecute, every data point we generate, and every compound we deliver is a step toward providing our partners with the scientific excellence they need to turn medical challenges into breakthroughs.

By Karen Lackey, CEO, X-Chem

Throughout this year, I have been reflecting on the resilience of our industry. In a year defined by market uncertainty, a shift has taken place: the “standard” approach to R&D is no longer enough. To navigate this landscape, discovery needs to be driven by large, multi-dimensional datasets and the new workflows required to achieve milestones faster.

Scaling data for better decisions

At X-Chem, we recognized that the antidote to market uncertainty is scientific certainty. To provide our partners with that clarity, we launched Chemomics. This platform was designed to move beyond simple hit-finding; it generates, manages, and interprets data on an unprecedented scale. By providing this informatics-driven foundation, we help our partners make better, faster, and more economical decisions, ensuring they move through the discovery funnel with confidence.

Global impact and productivity

Our mission to power drug discovery through DEL leadership, computational science, and chemistry excellence served a truly global customer base, stretching from North America to Japan, Australia, and across Europe.

Behind our success in delivering on 190 projects this year is the world-class expertise of our teams in Waltham, Montreal, and Budapest. Their dedication ensures that we remain committed to powering discovery regardless of the organizational model. In 2025, we focused on well-structured collaborations customized for the unique needs of our diverse partners:

• Academic groups and foundations seeking to translate foundational research;
• Biotech and venture capital teams focused on rapid de-risking and asset creation;
• Global pharma companies requiring industrial-scale discovery engines.

These collaborations spanned critical therapeutic areas, including oncology, cardiovascular disease, neurodegeneration, and the rapidly evolving field of obesity and metabolic health.

Innovation in the partnership model

Innovation requires not only technology but also a model that is “fit-for-purpose.” This year, we saw increasing demand toward our Builder programs (HitBuilder, LeadBuilder, CandidateBuilder). We created these options to provide a single-investment, outcome-based model that guarantees results within specified timeframes, offering a predictable, lower-risk alternative for partners when compared to the traditional FTE model.

Our selected 2025 milestones illustrate this versatility across the discovery spectrum:

• Integrated expansion: Building on a relationship established years prior, Orion extended their partnership with us in 2025, integrating computational chemistry for advanced lead optimization.
• Addressing unmet needs: We supported BioTryp in an anti-bacterial program, delivering specialized expertise for an area of high clinical urgency.
• Strategic alliances: We extended our reach through CRO alliances with Axxam, Cube Biotech, Charles River Laboratories, and Evotec. These collaborations allow us to scale delivery , extend geographic coverage, and support customer programs more efficiently worldwide.

Looking Ahead to 2026

The pharmaceutical industry has evolved to depend on high-quality, innovative platforms that are both economically and technically feasible. To our partners: thank you for your continued trust and for allowing us to be part of your journey toward the clinic.

Whether working with a seed-stage biotech or a global pharmaceutical leader, we are committed to high-quality delivery and earning long-term, productive partnerships. We look forward to continuing this philosophy to drive the creation of safe and efficacious medicines in 2026.

Scientists from X-Chem, in collaboration with researchers at AstraZeneca, RWTH Aachen University, University of Manchester and Instituto de Estudios Ambientales y Recursos Naturales, have developed a powerful new approach for making amine-containing heterocyclic compounds that are important ingredients in many pharmaceuticals and other high-value chemicals. The traditional methods for adding amine groups to heterocyclic rings like pyridines, pyrroles and furans have major limitations — they often require multiple steps, use harsh conditions, give poor yields and struggle with incorporating complex amine components.

The new strategy is published in Nature Catalysis. In the publication, the team circumvents these issues by taking a fundamentally different approach. Rather than modifying an existing heterocyclic aromatic ring, they start with readily available saturated heterocyclic ketones as building blocks. These ketones can easily be derivatized using standard carbonyl chemistry methods.

The key step is condensing the ketone with an amine component to form an “enamine” intermediate. This enamine then undergoes a remarkable sequence of mild photochemical oxidation and desaturation reactions, mediated by iridium and cobalt catalysts, to strip out hydrogens and form the desired amine-substituted heterocycle.

“Our method allows us to stitch in amine groups at positions that are very difficult to target using standard aromatic functionalization reactions,” said coauthor Augusto Hernandez-Perez, associate principal scientist at X-Chem. “And we can do it in just a single operation from simple precursors under mild conditions.”

Notably, the same mild reaction conditions could be applied to make a wide variety of valuable heterocyclic products, including pyridines, pyrroles, furans, thiophenes and pyrazoles substituted with primary and secondary amines. Even complex amine components like constrained piperidines and piperazines were well tolerated.

A Project Sprouting From a Hard Challenge and an Industry-Academia Discussion

The project serendipitously started in 2022 when Hernandez and his team struggled with late-stage functionalization of a pyrrolidine moiety.

“The challenge was to put an aryl group on the nitrogen of the pyrrolidine. Most C-N couplings such as Buchwald-Hartwig, Ullman, Chan-Lam-Evans and others failed,” said Hernandez.

The team found procedures published by Professor Daniele Leonori from the University of Manchester — A photochemical dehydrogenative strategy for aniline synthesis — and decided to give them a try, but the protocols, when used to arylate pyrrolidine moieties, provided low yields.

Hernandez reached out to Leonori and had several discussions. At the same time, the X-Chem team further investigated the scope of the photochemical strategy. Instead of generating aryl rings, they pivoted to generating pyridine rings. They quickly succeeded in discovering novel reaction conditions.

“The Leonori group had previously attempted synthesizing pyridine rings using the photochemical dehydrogenative strategy but failed. We shared our data, and they tried again in their lab. Within a week, they were able to obtain similar yields as ours, and we initiated the collaboration with Leonori’s group that resulted in this publication,” said Hernandez.

Allowing Easier Late-Stage Functionalization for Drug Discovery Programs

The collaborative team demonstrated the method on pharmaceuticals like the ADHD drug atomoxetine, the antidepressant paroxetine and the smoking cessation aid cytisine. They were able to efficiently add amine groups at key positions that would be very difficult to target otherwise.

“This desaturative coupling approach really opens up fundamentally new retrosynthetic disconnections for these invaluable heterocyclic substructures,” said Hernandez. “The strategy could streamline synthesis routes and allow easier late-stage functionalization for drug discovery programs.”

The work also provides fundamental new mechanistic insights into cooperativity between photoredox and cobalt catalysis pathways. Detailed studies suggest the cobalt catalyst plays two distinct roles — first activating the substrates via hydrogen atom transfer, and then facilitating key oxidation steps.

With its broad scope, mild conditions, simple starting materials and unique mode of amine installation, Leonori’s new method promises to significantly expand the tool kit for synthesizing high-value amine-containing heterocycles across pharmaceutical, agrichemical and materials applications. The study demonstrated how X-Chem supports drug discovery programs by collaborating with innovators to incorporate new synthetic methods to access compounds that are difficult to generate otherwise.

Synthetic Innovation Broadens Drug Discovery Project Success

Building upon our expertise and a commitment to quality and success, X-Chem has a strong track record (17 compounds reading IND-enabling toxicology studies and seven compounds progressing to Phase I or beyond) in developing and expanding hits derived from different hit identification methods, such as phenotypic screens, high-throughput screens, fragment screens, structure-based designs, chemo-proteomics, AI/ML generative models, structure-based designs and DNA-encoded chemical library screens.

If you are interested in learning more, please contact us and follow us on LinkedIn. No matter your indication of interest, we get hits to exponentially accelerate your drug discovery program.

X-Chem has been named the winner of the Best of Show Awards at the 2024 Drug Discovery Chemistry conference, which took place in San Diego in April 2024. The company’s offering, “DELability,” stood out among 13 other finalists.

The conference, attended by more than 900 participants working in pharma, biotech and academia worldwide, focuses on the discovery and optimization challenges of small molecules. As part of the conference, the Best of Show Award is an opportunity for the community to identify exceptionally innovative technologies used by life science professionals. The attendees vote on the most impactful new products.

“This offering has the potential to revolutionize the way scientists evaluate their targets for tractability,” said Anthony Keefe, SVP Innovation at X-Chem. “Our partners can expect a turnaround of results in 30 days. The results will infer if the target of interest is tractable and which targets, if there are multiple, to prioritize for hit identification. For the first time, drug hunters in the field of small molecule discovery can obtain relevant data that provide early assessment of target prior to a full investigational campaign, which can help them significantly de-risk their projects.”

Among the suite of drug discovery solutions X-Chem provides, DELability is differentiated by low investment, fast turnaround time and guaranteed results that can inform next steps. It evaluates targets and reports their suitability for DEL hit identification. This service is especially applicable for clients who have a large portfolio of targets, those who have challenging targets and wish to optimize screening conditions or those who are looking to prioritize constructs for a screen.

Machine learning has significant promise, but we should never overlook the importance of the human factor. Read more on what X-Chem’s subject matter experts think when it comes to humans vs. machines in drug discovery.