Design, Synthesis, and Biological Evaluation of a Cathepsin B-Activated Small Molecule-Drug Conjugate Targeting AKR1C3 to Enhance Chemotherapeutic Selectivity

Small molecule-drug conjugates (SMDCs) represent an emerging prodrug strategy for precision targeted therapy. In this study, we developed a series of cathepsin B (CTSB)-activated SMDCs targeting Aldo-keto reductase family 1 member C3 (AKR1C3). Among these conjugates, SM-27 was identified as the optimized compound, which exhibited excellent inhibitory activity against AKR1C3 with an inhibitory concentration value of 9 ± 2 nM and could efficiently release the payload gemcitabine under the mediation of CTSB. The antitumor activity of SM-27 was dually dependent on the expression of AKR1C3 and CTSB, allowing it to precisely recognize and eliminate tumor cells with low toxicity to normal cells. In vivo xenograft tumor assays with SM-27 showed significantly superior tumor inhibitory efficacy to gemcitabine with markedly lower off-target toxicity. In conclusion, this study proposes a novel design strategy for SMDCs targeting AKR1C3, which provides a highly promising research approach to address the off-target issue in chemotherapy.