Chemical control over immune recognition: a class of antibody-recruiting small molecules that target prostate cancer.
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 prostate-specific membrane antigen (PSMA) with high affinity (high pM to low nM), (2) template the formation of ternary complexes of 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.
Murelli
Ryan P
RP
Department of Chemistry, Yale University, 225 Prospect Street, P.O. Box 208107, New Haven, Connecticut 06520-8107, USA.
Zhang
Andrew X
AX
Michel
Julien
J
Jorgensen
William L
WL
Spiegel
David A
DA
D000912:Antibodies, Neoplasm / Q000276:immunology*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology
D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents