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

Abstract 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 α V β 3 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 α V β 3 . 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 α V β 3 over α 5 β 1 in a ratio of 1 : 4519 (ELISA) and showed selectivity for α V β 3 ‐positive WM115 cells over α V β 3 ‐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).