Journal of The AMerican Chemical
Chemically Synthesized Molecules with the Targeting and Effector Functions of Antibodies
Patrick J. McEnaney, Kelly J. Fitzgerald, Andrew X. Zhang, Eugene F. Douglass, Jr., Weifang Shan,
Aaron Balog, Mariya D. Kolesnikova, and David A. Spiegel
This article reports the design, synthesis, and evaluation of a novel class of molecules of intermediate size (approximately 700 Da), which possess both the targeting and effector functions of antibodies. These compounds -- called synthetic antibody mimics targeting prostate cancer (SyAM-Ps) -- bind simultaneously to prostate-specific membrane antigen and Fc gamma receptor I, thus eliciting highly selective cancer cell phagocytosis, SyAMs have the potential to combine the advantages of both small-molecule and biologic therapies, and may address many drawbacks associated with available treatments for cancer and other diseases.
Illuminating HIV gp120-ligand recognition through computationally-driven optimization of antibody-recruiting molecules
Christopher G. Paraker, Markus K. Dahlgren, Ran N. Tao, Don T. Li, Eugene F. Douglass, Jr. , Takuji Shoda, Navneet Jawanda, Kraimir A. Spasov, Sangil Lee, Nannana Zhou, Robert A. Domaoal, Richard E. Sutton, Karen S. Anderson, Mark Krystal, WIlliam L. Jorgensen and David A. Spiegel
Here we report on the structure-based optimization of antibody-recruiting molecules targeting HIV gp120 (ARM-H). These studies have leveraged a combination of medicinal chemistry, biochemical, and cellular assay analysis, and computation. Our findings have afforded an optimized analog of ARM-H, which is ~1000 fold more potent in gp120-binding and MT-2 antiviral assays than our previously reported derivative. Furthermore, computational analysis, taken together with experimental data, provides evidence that azaindole- and indole-based attachment inhibitors bind gp120 at an accessory hydrophobic pocket beneath the CD4-binding site and can also adopt multiple distinct binding modes in interacting with gp120. These results are likely to prove enabling in the development of novel HIV attachment inhibitors, and more broadly, they suggest novel applications for ARMs as probes of conformationally flexible systems.
A call to ARMs: the promise of immunomodulatory small molecules
David A. Spiegel
Small molecules possessing the properties of biologics hold promise for a wide range of therapeutic applications. Antibody-recruiting molecules (ARMs) -- "bifunctional" (two-headed) agents that can hijack antibody proteins -- represent one member of this group and have the potential to herald a new era in pharmaceutical design.
Reprogramming Urokinase into an Antibody-Recruiting Anticancer Agent
Charles E. Jakobsche, Patrick J. McEnaney, Andrew X. Zhang, and David A. Spiegel
Synthetic 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 targeting the urokinase-type plasminogen activator receptor (uPAR). Urokinase-type plasminogen activator (uPA) and uPAR are overexpressed on the surfaces of a wide range of invasive cancer cells and are believed to contribute substantially to the migratory propensities of these cells. The key component of our approach is an antibody-recruiting molecule that targets the urokinase receptor (ARM-U). This bifunctional construct is formed by selectively, covalently attaching an antibody-binding small molecule to the active site of the urokinase enzyme. We demonstrate that ARM-U is capable of directing antibodies to the surfaces of target cancer cells and mediating both antibody-dependent cellular phagocytosis (ADCP) and antibody cellular cytotoxicity (ADC) against multiple human cancer cell lines. We believe that the reported strategy has the potential to inform novel treatment options for a variety of deadly, invasive cancers.
ACS Chemical Biology
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. Schultz
Here 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 dinitrophenyl (DNP)-specific antibodies. When introduced into hu-PBL-NOD/SCID mice previously immunized with a KLH-DNP immunogen, this conjugate induced a targeted anti-body-dependent cellular cytotoxcity (ADCC) response to PSMA-expressing tumor cells in a mouse xenograft model. The ability to create a small molecule inducible antibody response against self-antigens using endogenous non-autoreactive antibodies may provide advantages over the autologous immune response generated by conventional vaccines in certain therapeutic settings.
ACS Chemical Biology
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 Cocleasa, William L. Joregnson, Jacek Lubkowski and David A. Spiegel
Prostate 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 targeting prostate cancer) that are capable of enhancing antibody-mediated immune recogition of prostate cancer cells. Interestingly, during the course of these studies, we found ARM-Ps to exhibit extraordinarily high potencies toward PSMA, compared to previously reported inhibitors. Here, we report in-depth biochemical, crystallographic, and computational investigations which elucidate the origin of the observed affinity enhancement. These studies reveal a previously unreported arene-binding site on PSMA, which we believe participates in an aromatic stacking interaction with ARMs. Although this site is composed of only a few amino acid residues, it drastically enhances small binding affinity. These results provide critical insights into the design of PSMA-targeted small molecules for prostate cancer diagnosis and treatment, more broadly, the presence of similar arene binding sites through the proteome could prove widley enabling in the optimization of small molecule-protein interactions.
Journal of the American Chemical Society (J|A|C|S)
Chemical Control over Immune Recognition: A Class of Antibody-Recruiting Small Molecules That Target Prostate Cancer
Ryan P. Murelli, Andrew X. Zhang, Julien Michel, William L. Jorgensen, and David A. Spiegel
Prostate cancer is the second leading cause of cancer-related death among the American male population, and it has been predicted that one out of every six American men will develop prostate cancer during their lifetime. Available treatment options, including chemical/surgical castration, radiation therapy, and chemotherapy, are often ineffective against advanced disease and are also often associated with severe side effects. Thus, new approaches to treat prostate cancer are highly desirable. To this end, monoclonal antibody therapies have shown promise; however, no such agent has yet successfully obtained FDA approval for the treatment of prostate cancer. Furthermore, antibody drugs are limited by severe side effects, lack or oral bioavailability, and high cost. Here we describe a novel technology for prostate cancer treatment that we believe could address many of the limitations of currently available therapies and that combines advantages of both small-molecule-based and antibody-based strategies.
Journal of The American Chemical Society (J|A|C|S)
An Antibody-Recruiting Small Molecule That Targets HIV gp120
Christopher G. Parker, Robert A. Domaoal, Karen S. Anderson, and David A. Spiegel
In recent years, antibody-based therapeutics have become important instruments in treating human disease. These approaches suffer from certain limitations, including severe side effects, lack of oral bioavailability, and high cost. Thus, alternative small-molecule-based methods that exploit the powerful cytolytic potential of antibodies already present in the human bloodstream could address many of these disadvantages.