Design, Synthesis, and In Vitro Evaluation of a PSMA‐Targeted Doxorubicin Conjugate

Clinical treatment of prostate cancer, particularly metastatic castration‐resistant prostate cancer (mCRPC), mainly depends on targeting prostate‐specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII). Toward this, small molecule–drug conjugates (SMDCs), consisting of a PSMA‐targeting ligand along with a chemotherapeutic, have emerged as an important targeted therapeutic tool. Herein, we have designed 39 ligands with varied targeting heads and linkers and have analyzed their efficacy in silico using molecular docking and molecular dynamics simulation. The best‐docked compound was further synthesized, conjugated with doxorubicin via an acid‐labile imine linkage to yield a novel PSMA–Dox conjugate. This conjugate was evaluated in vitro in PSMA‐positive (LNCaP and C4‐2 cells) and PSMA‐negative (PC3 cells) to establish its selectivity toward PSMA, as well as to ascertain its selective cytotoxicity toward PSMA‐positive cells. Further, cell cycle analysis confirmed the efficacy of the conjugate to induce apoptosis in PSMA‐positive cancer cells. Thus, this study demonstrates a new SMDC which can serve as a template for creating new analogs with enhanced targeting and anticancer efficacy.