Abstract

THIENOPYRIMIDINES AS WARHEADS IN PROTACS: A MEDICINAL CHEMISTRY PERSPECTIVE

Priya A.*, Mahesh Kumar N. and Dr. Shachindra L. Nargund

ABSTRACT

Targeted protein degradation (TPD) represents a transformative approach in modern drug discovery, enabling the selective elimination of pathogenic proteins rather than merely inhibiting their activity. Among TPD strategies, Proteolysis Targeting Chimeras (PROTACs) have garnered substantial interest due to their ability to induce catalytic, event-driven protein degradation via the ubiquitin–proteasome system. As research in this domain evolves, thienopyrimidine scaffolds have gained recognition as promising warheads within PROTACs, attributed to their established role as ATP-competitive kinase inhibitors and favourable pharmacokinetic profiles. This review provides a focused analysis of the design and development of thienopyrimidine-based PROTACs, particularly those targeting key oncogenic kinases such as EGFR, VEGFR2, and PI3K. We highlight the synthetic versatility of thienopyrimidines and their compatibility with click chemistry, which allows for modular PROTAC construction and linker optimization. Key parameters influencing PROTAC performance, including linker length, orientation, exit vector positioning, and the selection of E3 ligases such as CRBN and VHL, are critically examined. We also explore recent structure-activity relationship (SAR) studies, advances in ternary complex formation, and structural innovations that enhance target specificity and degradation efficiency. Challenges such as off-target effects, limited bioavailability, and resistance mechanisms are addressed, alongside strategies to overcome these limitations. In addition, we review next-generation degraders such as molecular glues, LYTACs, AUTACs, and photoPROTACs, which broaden the scope of TPD. By combining advances in medicinal chemistry with emerging strategies in targeted protein degradation, this review highlights the potential of thienopyrimidines as versatile scaffolds for developing selective and efficacious degraders in oncology and broader therapeutic areas.

Keywords: E3 ligases, EGFR, Modern drug discovery, PROTACs, Targeted protein degradation, Thienopyrimidine, VEGFR2.