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Chemical Control over Immune Recognition: A Class of Antibody-Recruiting Small Molecules That Target Prostate Cancer
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Section:Abstract
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.
Citing Articles
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This article has been cited by 5 ACS Journal articles (5 most recent appear below).
A Chemically Induced Vaccine Strategy for Prostate Cancer
Anna Dubrovska, Chanhyuk Kim, Jimmy Elliott, Weijun Shen, Tun-Hsun Kuo, Dong-In Koo, Chun Li, Tove Tuntland, Jonathan Chang, Todd Groessl, Xu Wu, Vanessa Gorney, Teresa Ramirez-Montagut, David A. Spiegel, Charles Y. Cho, and Peter G. SchultzACS Chemical Biology2011 6 (11), 1223-1231A Chemically Induced Vaccine Strategy for Prostate Cancer
Anna Dubrovska, Chanhyuk Kim, Jimmy Elliott, Weijun Shen, Tun-Hsun Kuo, Dong-In Koo, Chun Li, Tove Tuntland, Jonathan Chang, Todd Groessl, Xu Wu, Vanessa Gorney, Teresa Ramirez-Montagut, David A. Spiegel, Charles Y. Cho, and Peter G. SchultzACS Chemical Biology2011 6 (11), 1223-1231Here we report the design and evaluation of a bifunctional, small molecule switch that induces a targeted immune response against tumors in vivo. A high affinity ligand for prostate specific membrane antigen (PSMA) was conjugated to a hapten that binds ...
Reprogramming Urokinase into an Antibody-Recruiting Anticancer Agent
Charles E. Jakobsche, Patrick J. McEnaney, Andrew X. Zhang, and David A. SpiegelACS Chemical Biology2011 Article ASAPReprogramming Urokinase into an Antibody-Recruiting Anticancer Agent
Charles E. Jakobsche, Patrick J. McEnaney, Andrew X. Zhang, and David A. SpiegelACS Chemical Biology2011 Article ASAPSynthetic compounds for controlling or creating human immunity have the potential to revolutionize disease treatment. Motivated by challenges in this arena, we report herein a strategy to target metastatic cancer cells for immune-mediated destruction by ...
Supramolecular Complexing of Membane Siglec CD22 Mediated by a Polyvalent Heterobifunctional Ligand that Templates on IgM
Lina Cui, Pavel I. Kitov, Gladys C. Completo, James C. Paulson, and David R. BundleBioconjugate Chemistry2011 22 (4), 546-550Supramolecular Complexing of Membane Siglec CD22 Mediated by a Polyvalent Heterobifunctional Ligand that Templates on IgM
Lina Cui, Pavel I. Kitov, Gladys C. Completo, James C. Paulson, and David R. BundleBioconjugate Chemistry2011 22 (4), 546-550We report the synthesis and in vitro evaluation of a multivalent homing device, a polymer which contains preordered pendant groups with dual specificity, a trisaccharide moiety, which is specific for the siglec CD22, and an antibody specific hapten, ...
A Biosynthetic Strategy for Re-engineering the Staphylococcus aureus Cell Wall with Non-native Small Molecules
James W. Nelson, Alexander G. Chamessian, Patrick J. McEnaney, Ryan P. Murelli, Barbara I. Kazmiercak, and David A. SpiegelACS Chemical Biology2010 5 (12), 1147-1155A Biosynthetic Strategy for Re-engineering the Staphylococcus aureus Cell Wall with Non-native Small Molecules
James W. Nelson, Alexander G. Chamessian, Patrick J. McEnaney, Ryan P. Murelli, Barbara I. Kazmiercak, and David A. SpiegelACS Chemical Biology2010 5 (12), 1147-1155Staphylococcus aureus (S. aureus) is a Gram-positive bacterial pathogen that has emerged as a major public health threat. Here we report that the cell wall of S. aureus can be covalently re-engineered to contain non-native small molecules. This process ...
A Remote Arene-Binding Site on Prostate Specific Membrane Antigen Revealed by Antibody-Recruiting Small Molecules
Andrew X. Zhang, Ryan P. Murelli, Cyril Barinka, Julien Michel, Alexandra Cocleaza, William L. Jorgensen, Jacek Lubkowski and David A. SpiegelJournal of the American Chemical Society2010 132 (36), 12711-12716A Remote Arene-Binding Site on Prostate Specific Membrane Antigen Revealed by Antibody-Recruiting Small Molecules
Andrew X. Zhang, Ryan P. Murelli, Cyril Barinka, Julien Michel, Alexandra Cocleaza, William L. Jorgensen, Jacek Lubkowski and David A. SpiegelJournal of the American Chemical Society2010 132 (36), 12711-12716Prostate specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase overexpressed in many forms of prostate cancer. Our laboratory has recently disclosed a class of small molecules, called ARM-Ps (antibody-recruiting molecule ...
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History
- Published In Issue December 02, 2009
- Article ASAPNovember 04, 2009
- Received: August 12, 2009
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