Linker attachment points: "finishing touch" in PROTAC design

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Drug Discovery

Background:

• Proteolysis-targeting chimera (PROTAC) technology utilizes targeted protein degradation via ubiquitination and proteasomal pathways.
• Current PROTAC development is hampered by empirical design, high molecular weight, and poor pharmacokinetic properties, necessitating linker optimization.
• Existing reviews often overlook linker attachment points, a critical factor for ternary complex formation, degradation efficiency, and selectivity.

Purpose of the Study:

• To systematically analyze the impact of linker attachment points on PROTAC performance.
• To provide structure-based rational design rules for linker attachment engineering.
• To guide the development of orally bioavailable PROTACs.

Main Methods:

• Focus on linker attachment sites of target protein ligands (POI) and E3 ligase ligands (CRBN, VHL, IAP).
• Elaboration of how anchoring site location and composition influence degradation and pharmacokinetics.
• Summarization of systematic, structure-based design principles.

Main Results:

• The location and chemical nature of linker attachment points significantly modulate PROTAC degradation efficacy and pharmacokinetic profiles.
• Systematic structure-based design rules for linker attachment engineering were summarized.
• This work addresses a gap in specialized reviews concerning PROTAC linker attachment.

Conclusions:

• Optimizing linker attachment points is crucial for enhancing PROTAC degradation performance and oral bioavailability.
• This review offers practical theoretical guidance for developing next-generation clinical PROTAC degraders.
• Rational design of PROTACs, particularly linker attachment, is key to overcoming current limitations.