RGD Peptidomimetic MMAE-Conjugate Addressing Integrin αVβ3-Expressing Cells with High Targeting Index**

Small molecule-drug conjugates (SMDCs) mimicking the RGD sequence (-Arg-Gly-Asp-) with a non-peptide moiety require a pharmacophore-independent attachment site. A library of 36 sulfonamide-modified RGD mimetics with nM to pM affinity for integrin αVβ3 was synthesized and analysed via DAD mapping. The best structure of the conjugable RGD mimetic was used and a linker was attached to an aromatic ring by Negishi cross-coupling. The product retained high affinity and selectivity for integrin αVβ3. The conjugable RGD mimetic was then attached to an enzymatically cleavable GKGEVA linker equipped with a self-immolative PABC and the antimitotic drug monomethyl auristatin E (MMAE). The resulting SMDC preferred binding to integrin αVβ3 over α5β1 in a ratio of 1 : 4519 (ELISA) and showed selectivity for αVβ3-positive WM115 cells over αVβ3-negative M21-L cells in the in vitro cell adhesion assay as well as in cell viability assays with a targeting index of 134 (M21-L/WM115).