2025 Review Illuminates Metabolism of PROTACs, Oligonucleotides, Macrocyclic Peptides, and Conjugated Drugs
Background
New drug modalities (NDMs) are revolutionizing pharmacology by targeting previously "undruggable" proteins and offering innovative treatments for diverse diseases. However, their complex structures often lead to unique metabolic pathways and tissue distribution profiles, posing significant challenges for drug development. A comprehensive understanding of NDM metabolism is crucial for predicting pharmacokinetics, ensuring safety, and optimizing therapeutic efficacy, bridging the gap between novel discovery and successful clinical application.
Study Design
This third annual review synthesized 15 selected publications from 2025, categorizing advances in new drug modality (NDM) metabolism into four key areas. The authors focused on PROTACs and molecular glues, oligonucleotide therapeutics, macrocyclic peptides, and conjugated drugs (including antibody-drug conjugates and Fc-fusion proteins). The review systematically analyzed research emphasizing biotransformation, chiral stability, in vitro/in vivo metabolic pathways, metabolite identification workflows, throughput enhancements, and leader-independent cyclization strategies across these complex modalities.
Results
The review highlighted significant progress in understanding NDM metabolism, crucial for their clinical translation. For PROTACs and molecular glues, key insights emerged regarding their biotransformation pathways and the critical role of chiral stability in their pharmacological profiles. In the realm of oligonucleotide therapeutics, the review detailed advancements in both in vitro and in vivo metabolic studies, alongside the development of a structured workflow for comprehensive metabolite identification. Macrocyclic peptides saw notable improvements in throughput enhancements for their synthesis and characterization, as well as novel approaches to leader-independent cyclization. > The collection provides critical insights into metabolism, tissue distribution, and analytical innovations intended to accelerate the transition of these complex modalities from discovery to clinical application. Finally, for conjugated drugs, the review encompassed advancements in the metabolism of antibody-drug conjugates (ADCs) and novel Fc-fusion proteins, addressing their unique degradation and distribution characteristics.
Key Findings
- Advances in PROTAC and molecular glue metabolism, emphasizing biotransformation and chiral stability.
- Improved understanding of oligonucleotide therapeutics' in vitro/in vivo metabolism and metabolite identification workflows.
- Throughput enhancements and leader-independent cyclization strategies for macrocyclic peptides.
- Metabolic insights into conjugated drugs, including antibody-drug conjugates (ADCs) and Fc-fusion proteins.
- Overall, critical insights into NDM metabolism, tissue distribution, and analytical innovations to accelerate clinical translation.
Why It Matters
This comprehensive review provides a vital roadmap for researchers and developers working with new drug modalities, offering consolidated insights into their metabolic fate. Understanding these complex metabolic pathways is paramount for optimizing drug design, predicting pharmacokinetics, and ensuring the safety of future therapeutics. For biohackers and clinicians, this knowledge underpins the rational development of next-generation treatments, potentially influencing how novel compounds are formulated, dosed, and monitored. The analytical innovations highlighted will accelerate the translation of these promising modalities from preclinical discovery to viable clinical protocols, ultimately expanding the therapeutic arsenal against challenging diseases.
new drug modalities
drug metabolism
protacs
oligonucleotides
macrocyclic peptides
conjugated drugs