Emerging Drug Modalities Redefining Small-Molecule Therapeutics: Antibody–Drug Conjugates, Protacs, and Molecular Glues

The landscape of drug discovery is undergoing a profound transformation with the emergence of new therapeutic modalities that extend beyond traditional occupancy-driven pharmacology. Antibody–drug conjugates (ADCs), proteolysis-targeting chimeras (PROTACs), and molecular glues exemplify this shift, emphasizing linker engineering, controlled payload release, and proximity-induced biological effects rather than classical high-affinity inhibition. These modalities harness endogenous cellular systems—such as targeted delivery mechanisms and the ubiquitin–proteasome pathway—to achieve enhanced specificity and catalytic or event-driven pharmacology. This paper provides a comprehensive examination of these innovative platforms, discussing their mechanistic principles, design strategies, materials and methods commonly employed in their development, experimental outcomes from representative case studies, and broader implications for future therapeutic innovation. The findings suggest that proximity-based and targeted degradation approaches offer distinct advantages in addressing undruggable targets, overcoming resistance mechanisms, and improving therapeutic indices. However, challenges related to stability, pharmacokinetics, immunogenicity, and largescale manufacturing remain significant. Continued integration of chemical biology, structural modeling, and translational pharmacology will be essential to fully realize the potential of these transformative drug modalities.

Antibody–drug conjugates; PROTACs; Molecular glues; Targeted protein degradation; Linker chemistry; Controlled release; Proximity pharmacology; Ubiquitin–proteasome system; Event-driven therapeutics; Precision medicine.

1. Burslem, G. M.; Crews, C. M. Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery. Cell 2020. [Google Scholar] [Crossref]

2. Chari, R. V. J.; Miller, M. L.; Widdison, W. C. Antibody–Drug Conjugates: An Emerging Concept in Cancer Therapy. Angew. Chem. Int. Ed. 2014. [Google Scholar] [Crossref]

3. Coley, C. W.; et al. Autonomous Discovery in the Chemical Sciences. Science 2020. [Google Scholar] [Crossref]

4. Dale, B.; Cheng, M.; Park, K. S.; Kaniskan, H. U.; Xiong, Y.; Jin, J. Advancing Targeted Protein Degradation for Cancer Therapy. Nat. Rev. Cancer 2021. [Google Scholar] [Crossref]

5. Krönke, J.; et al. Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells. Science 2014. [Google Scholar] [Crossref]

6. Mullard, A. Targeted Protein Degraders Crowd into the Clinic. Nat. Rev. Drug Discov. 2021. [Google Scholar] [Crossref]

7. Senter, P. D.; Sievers, E. L. The Discovery and Development of Brentuximab Vedotin for Relapsed Hodgkin Lymphoma. Nat. Biotechnol. 2012. [Google Scholar] [Crossref]

8. Sun, X.; Gao, H.; Yang, Y.; He, M.; Wu, Y.; Song, Y.; Tong, Y.; Rao, Y. PROTACs: Great Opportunities for Academia and Industry. Signal Transduct. Target. Ther. 2019. [Google Scholar] [Crossref]

9. Toure, M.; Crews, C. M. Small-Molecule PROTACs: New Approaches to Protein Degradation. Angew. Chem. Int. Ed. 2016. [Google Scholar] [Crossref]

• Drone-Based Phenotyping and its Utilization in Crop Improvement: A Review
• An IoT-Enabled Smart Healthcare Monitoring System Using Machine Learning for Early Health Risk Prediction
• Strategic Integration of Artificial Intelligence for Achieving Operational Excellence in Container Freight Stations Using Evidence from Chennai, India
• Adoption of OTT platforms: Analyzing User Behavior through the UTAUT2 Model
• Customers’ Buying Behaviour in Relation to Online Food Delivery (Evidence from National Capital Region (NCR) of India)