Mono-amino acid linkers enable highly potent small molecule-drug conjugates by conditional release.

ABSTRACT: The endosome cleavable linkers have been widely employed by antibody-drug conjugates and small molecule-drug conjugates (SMDCs) to control the accurate release of payloads. An effective linker should provide stability in systemic circulation but efficient payload release at its targeted tumor sites. This conflicting requirement always leads to linker design with increasing structural complexity. Balance of the effectiveness and structural complexity presents a linker design challenge. Here, we explored the possibility of mono-amino acid as so far the simplest cleavable linker (X-linker) for SMDC-based auristatin delivery. Within a diverse set of X-linkers, the SMDCs differed widely in bioactivity, with one (Asn-linker) having significantly improved potency (IC₅₀ = 0.1 nM) and fa

SUBMITTER: Zheng Y 

PROVIDER: S-EPMC11163218 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature