The emergence of proteolysis-targeting chimeras (PROTACs) has changed the way researchers approach the handling of disease-causing proteins. This novel drug type offers a fresh strategy for degrading proteins that were previously considered “undruggable,” representing exciting advancements in the industry and giving hope to patients suffering from debilitating conditions.
However, the unique structure and complexity of PROTACs present challenges in navigating the path to IND submission. Early-stage PROTAC drug development considerations include addressing analytical and characterization issues, detecting stability and metabolism, and evaluating the druggability of PROTACs.
Later stages in the process, as these drugs progress towards an IND submission, also require great care, and developers should seek expertise in risk mitigation and insights into translational strategies and organizational readiness.
1. Manage Off-target and On-Target Toxicity
PROTACs, by their nature, come with risk. If a target plays a role in essential cellular functions, its degradation can lead to irreversible consequences. Unintended toxicity can arise even from the low-level degradation of essential or partially homologous proteins. E3 ligases also carry risk, as their recruitment may lead to off-target ubiquitination and degradation. Finally, linker chemistry can also contribute to toxicity by forming reactive or unstable intermediates.
Several strategies can be employed during the preclinical stage to mitigate on-target and off-target toxicities.
- Global proteomic profiling: Increasingly applied to map the degradation profile across cell types and species, allowing for early identification of unintended protein targets.
- Functional genomics screens: Assess gene essentiality in disease-relevant and normal tissues, providing valuable insights about possible on-target liabilities.
- Incorporating delivery strategies: Nanoparticles, antibody-PROTAC conjugates, or prodrug formulations help modulate tissue distribution and reduce exposure to non-target organs, especially when systemic degradation poses a safety risk.
- Metabolite identification studies: Crucial for detecting toxic degradation products or reactive linker-derived fragments.
- Tissue cross-reactivity and biodistribution studies: Essential for evaluating unintended effects in non-target organs, especially when E3 ligases or target proteins are expressed outside the intended therapeutic window.
2. Select the Right E3 Ligases
PROTAC development usually relies on a few well-characterized E3 ligases, such as VHL and CRBN. However, these may not provide tissue-specific degradation, potentially resulting in unwanted degradation in non-target tissues.
The industry is now seeking novel E3 ligases with restricted tissue expression to minimize off-target effects. Current efforts focus on identifying ligases with tissue- or disease-specific profiles, while structure-based screening is being used to discover new ligands and chemotypes for less-characterized E3s.
3. Utilize the Latest Technology
PROTAC discovery is increasingly time-consuming and resource-intensive. Many researchers are turning to computational and machine learning tools to accelerate the early-stage development process. Common applications are the prediction of ternary complex formation, the assessment of degradation potential, and informing the design of optimal linkers and ligands before compounds are synthesized.
Machine learning platforms can help prioritize candidates with the highest likelihood of success by integrating diverse data sources, from structural models to cellular degradation outcomes. These approaches are still evolving but are already helping reduce reliance on broad empirical screening, streamlining the path to more effective PROTACs.
4. Ensure Integration and Cross-Functional Planning
To achieve a successful IND submission, researchers must seamlessly integrate chemical optimization, ADME characterization, analytical method development, and toxicology. Establishing and maintaining cross-functional collaboration early on is essential to navigating the path to the clinical stages and ensuring that degradation efficiency is not pursued at the expense of safety or bioavailability.
Best practices include early alignment on developability thresholds, the real-time integration of bioanalytical, DMPK, and efficacy data into decision-making frameworks, and the adoption of scoring or ranking systems to compare candidates holistically.
A Final Word
The recent New Drug Application (NDA) submission of the first-ever PROTAC drug has marked a significant regulatory milestone for this new therapeutic modality. The promise of PROTACs is now beginning to be realized, as more treatments edge closer to making a difference in the lives of patients. However, the path remains far from straightforward. PROTACs are powerful drugs, but their development involves carefully assessing and mitigating risk. Thankfully, new technologies, cross-functional planning, and the correct organizational approach can help tackle these hurdles, allowing for an easier path to IND submission and eventually to NDA.
