VH032-thiol-C6-NH2

Background Introduction

VH032-thiol-C6-NH2 is a specially designed E3 ligase ligand-linker conjugate widely used in the development of PROTACs (Proteolysis Targeting Chimeras). Featuring a VH032 moiety (a highly validated ligand for the Von Hippel-Lindau [VHL] E3 ligase) tethered via a flexible hexyl (C6) linker and terminating in a thiol and amine group, this compound enables precise and versatile conjugation chemistry. Its unique functional groups provide essential reactive handles for further PROTAC assembly, supporting the efficient targeting and removal of disease-relevant proteins.

Mechanism

VH032-thiol-C6-NH2 operates as a modular building block in PROTAC synthesis. The VH032 unit non-covalently binds to the substrate recognition domain of the VHL E3 ubiquitin ligase complex. The hexyl (C6) linker offers spatial flexibility, while the terminal thiol and amine functionalities allow for selective coupling to various warheads or target-binding ligands via amide or thioether linkages. Upon successful conjugation, the resulting PROTAC molecule mediates target protein ubiquitination by recruiting the E3 ligase into close proximity with the protein of interest, marking it for subsequent proteasomal degradation.

Applications

VH032-thiol-C6-NH2 is extensively utilized in targeted protein degradation research and PROTAC platform development. Its customizable linker system facilitates the rapid synthesis of diverse PROTACs for high-throughput screening, medicinal chemistry optimization, and in vitro/in vivo functional studies. Typical applications include designing PROTAC tool compounds for oncology, neurodegenerative diseases, immunology, and other therapeutic indications where protein degradation offers a unique intervention strategy. Additionally, its reactive handles support site-specific conjugation and enable seamless integration into bifunctional chimeric molecules for drug discovery and development.

• Thiol-functionalized VH032 derivative enables efficient covalent attachment to diverse payloads for flexible PROTAC design.
• C6 amine linker tailored for improved solubility and optimal E3 ligase engagement in VHL-based PROTAC synthesis.