Chemical Control Over Immune Recognition: A Class of Antibody-Recruiting Small Molecules (ARMs) that Target Prostate Cancer

摘要

Prostate cancer is the second leading cause of cancer-related death among the American male population, and society is in dire need of new approaches to treat this disease. Here we report the design, synthesis, and biological evaluation of a class of bifunctional small molecules, called antibody-recruiting molecules targeting prostate-cancer (ARM-Ps), that enhance the recognition of prostate cancer cells by the human immune system. ARM-P derivatives were designed rationally via the computational analysis of crystallographic data, and we demonstrate here that these materials are able to: (1) bind PSMA with high affinity (high pM to low nM), (2) template the formation of ternary complexes between anti-DNP antibodies, ARM-P, and LNCaP human prostate cancer cells, and (3) mediate the antibody-dependent killing of LNCaP cells in the presence of human effector cells. This manuscript describes the application of fundamental chemical principles to the design of a novel class of molecules with high therapeutic potential. We believe that this general small-molecule-based strategy could give rise to novel directions in treating cancer and other diseases.