Sigma-2 receptor ligand drug conjugates as antitumor compounds, methods of synthesis and uses thereof
Abstract:
Methods and compositions for treating cancers such as pancreatic cancer and synovial sarcoma are disclosed. Compounds comprising a sigma-2 receptor-binding moiety and a ferroptosis-inducing moiety are described, such as the methanesulfonate salt of a compound of structural Formula IV, , wherein n is an integer chosen from 1, 2, 3, 4, and 5, and R2 is H or methyl. At least one described molecular species exhibits an IC50 value below 5 μM against human pancreatic cancer cells in vitro. Administration of this species promoted shrinkage of pancreatic cancer tumors in a murine model system in vivo. It led to a 100% survival of experimental animals over a time course in which control therapies provided only 30% or 40% survival. Methods of synthesis of molecular species are also disclosed.
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