Hitting the bullseye: PSMA-targeted small molecule drug conjugate for prostate cancer treatment

Prostate-specific membrane antigen (PSMA) is a significantly overexpressed receptor in prostate cancer, making it an ideal target. Hence, targeted delivery of a payload via a small molecule to PSMA would facilitate localized cytotoxicity, thereby eradicating the tumor. Herein, we describe a small-molecule drug conjugate (DUPA-SS-Exa, 10) comprising 2-[3-(1,3-dicarboxy propyl)-ureido]pentanedioic acid (DUPA), a PSMA binding ligand, conjugated to exatecan (8) payload via a glutathione-sensitive disulfide traceless linker. Exatecan (8) has been extensively delivered via antibody-drug conjugates (ADCs) and has shown favourable results. The DUPA-SS-Exa (10) conjugate was computationally evaluated to assess PSMA binding affinity in a dynamic environment, and ΔG _bind was found to be -115.85 ± 4.52 kcal mol^-1. An in vitro cell cytotoxicity assay performed against the PSMA-positive LNCaP cell line showed an IC₅₀ of 117.01 ± 6.67 nM for conjugate (10). DUPA-SS-Exa (10) demonstrated high specificity, showing negligible cytotoxicity against PSMA-negative PC3 cells and non-cancerous HEK293 cells. Furthermore, DUPA-SS-Exa (10) is stable at acidic pH, in PBS, and in serum. Beyond its stability, the conjugate proved significantly safer than free exatecan (8) in B16F10 melanoma models, while exatecan (8) caused severe toxicity, leading to significant weight loss and mortality in mice models. These results establish DUPA-SS-Exa (10) as a stable, highly specific, and potent therapeutic strategy for PSMA-expressing tumors with a favorable safety profile.