It is much faster and less expensive to address chemotype-based risk factors in the lead optimization phase than later on. Too frequently, such issues are found to have originated from predictable (and thus avoidable) risk factors. Furthermore, the later such risk issues are identified (in the Hit Identification→Hit Identification phases), the fewer options the team has. Our unrelenting focus is to deliver maximally de-risked clinical candidates for IND-enabling studies and beyond. Since 2010, X-Chem scientists were named as co-inventors on 16 of our clients’ projects and 6 clinical candidates are advancing in IND-enabling tox. Critical elements of our analysis and forward-risk assessment include:
- Target pharmacology: High potency optimization — while typically the easiest aspect to achieve — must be driven holistically using the most therapeutically relevant assays and pharmacological parameters (not just EC50 or IC50 from engineered cell lines). This requires thorough understanding of the in vitro assays, disease models, off-targets and overall target biology. Considerations such as kinetics, mode of action and signaling pathways are critical.
- In vitro DMPK: Projects progress fastest and best when logical and predictive correlations can be made between in vitro profiling characteristics and in vivo properties. Alternatively, in cases where such correlations are challenging, efforts to investigate can often lead to enabling discoveries.
- Assure high passive permeability and high solubility
- Minimize transporter interactions and metabolism
- Safety: Discovery of toxicity is still a frequent factor in late-stage attrition. Therefore, it is essential that safety assessment begins from initial hit identification and continues at every stage.
- Proactively separate tox concern from target affinity and monitor genotox, non-specific tox, cyto/mitotox and reactive metabolite formation (both predictable and actual)
- Eliminate off-target activity, including target subtypes, cardiac channels, CYP and transporter modulators, and more broadly through safety panels.
- Optimization of efficacy and safety of covalent drugs
- Target engagement: Maximize receptor occupancy and ensure the free drug concentration and duration at the site of action align with the target-specific PK/PD strategy. We have specialized expertise in CNS therapeutics and drugs targeting the liver and GIT.
- Translational strategy: An early understanding of the translational path (biomarker, translational imaging, or translational PK/PD models) can help align ongoing assay and compound optimization with translational tool development, expediting the delivery of drug candidates that are optimally suited for proof-of-concept studies.
Structure-Based Drug Discovery
IntelliSyn uses structure-based drug discovery (SBDD) techniques to prioritize synthetic targets with structural rationale, ensuring synthesis plans are filtered and focused toward only the most project-advancing compounds.
SBDD involves the use of structural biology information to guide the design of new and improved compounds. Three-dimensional structural information, coupled with expert computational and medicinal chemistry insight, can greatly accelerate project advancement.
- Our experienced scientists utilize SBDD and related in silico approaches at all stages of the project for hit identification, hit-to-lead and lead optimization.
- Through our partnership with Proteros, we can add protein production, X-ray crystallography and cryo-EM services into projects to speed up 3D structural understanding and shorten project timelines.
Effective Data and Information Sharing Is Critical
The rate of scientific progress continually accelerates; fast-moving projects must respond to evolving priorities with agility. It takes experienced management and effective data handling infrastructure to turn data into decision-enabling knowledge.
All our team members employ SciFinder, Reaxys and other chemical databases. For compound synthesis, we use specialized project IT management tools to track the progress of each compound from idea, design, prioritization, synthesis and finally to registration.
All synthetic procedures and characterization are captured in cloud-hosted, countersigned and encrypted electronic vaults. Registration data, along with all predicted properties, in vitro SAR-driving test results and in vivo studies are encrypted and stored in our cloud-hosted databases. When it is time to write the patent or publication, all information is exported in submission-ready format. All this information is fully scalable as the project grows and is completely and transparently accessible to the collaborator at any time.
Custom Synthesis and Process Route Development
Several top-10 major pharmaceutical organizations and numerous biotechnology firms rely on X-Chem to solve their most difficult and IP-sensitive synthetic challenges. 80% of our scientists have PhDs from top universities in North America and Europe, and we take pride in our expertise in asymmetric catalysis, natural products, total synthesis, process development, and organometallic chemistry.
Our pharmaceutical and biotechnology clients rely on X-Chem for process improvement and scale-up excellence. In our kilo-lab suite we prepare up to 500 g of API, and we work closely with a netword of CMOs to ensure fast and reliable transfer to plant scale. We have a strong track record in successfully developing vastly shorter and more efficient multi-step process, frequently through novel enantioselective methods.
- Flow chemical reactors
- Pilot reactors up to 15 liters (-50 degrees C to 100 degrees C)
- Multi-gram chiral SFC chromatography
-Robust and reproducible methods ready for transfer to process team