A targeted drug conjugate derived from GNS561 and a Pt(II) moiety for PPT1-mediated lysosomal autophagy inhibition in triple-negative breast Cancer

Triple-negative breast Cancer (TNBC) represents a formidable oncological threat, distinguished by its elevated malignancy and limited therapeutic outlook for female patients. The efficacy of conventional therapeutic regimens including surgery and targeted small-molecule inhibitors is often compromised by severe adverse systemic effects and the acquisition of drug resistance. Guided by the concept of targeted drug conjugates (TDCs), we engineered GN-604 through the covalent integration of a Pt(II) pharmacophore into the molecular scaffold of GNS561, a known Autophagy inhibitor. GN-604 selectively inhibits palmitoyl-protein thioesterase 1 (PPT1) both in vitro and in vivo, leading to lysosomal dysfunction and Autophagy inhibition. Furthermore, GN-604 facilitates the targeted intracellular sequestration of Pt(II), thereby triggering robust DNA lesions and suppressing malignant cell expansion. In vivo evaluations utilizing a MDA-MB-231 xenograft model demonstrated that GN-604 achieved superior antitumor potency to GNS561, cisplatin, or their co-administration. In summary, GN-604 emerges from this study as an encouraging bifunctional therapeutic modality tailored for the management of aggressive TNBC.