A call to ARMs: the promise of immunomodulatory small molecules

Spiegel, David A.

doi:10.1586/ecp.13.10

Cited by 6 publications

(2 citation statements)

References 19 publications

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“…Similarly, PROTAC-induced enzyme reprogramming parallels the mechanism by which cyclosporine and tacrolimus (FK-506) bind to their respective immunophilin targets (cyclophilin and FKBP12) and facilitate subsequent association with calcineurin. This concept of induced functional interaction of two proteins to upregulate a specific biological pathway may find numerous other applications; indeed, it has also been demonstrated, in an extracellular sense, with the recruitment of antibodies 35 mediated by PROTAC-like chimeric agents that bind cell surface receptors and display hapten, promoting the binding of antibodies and subsequent immune system mobilization.…”

Section: Discussionmentioning

confidence: 99%

Catalytic in vivo protein knockdown by small-molecule PROTACs

et al. 2015

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The current predominant theapeutic paradigm is based on maximizing drug-receptor occupancy to achieve clinical benefit. This strategy, however, generally requires excessive drug concentrations to ensure sufficient occupancy, often leading to adverse side effects. Here, we describe major improvements to the proteolysis targeting chimeras (PROTACs) method, a chemical knockdown strategy in which a heterobifunctional molecule recruits a specific protein target to an E3 ubiquitin ligase, resulting in the target’s ubiquitination and degradation. These compounds behave catalytically in their ability to induce the ubiquitination of super-stoichiometric quantities of proteins, providing efficacy that is not limited by equilibrium occupancy. We present two PROTACs that are capable of specifically reducing protein levels by >90% at nanomolar concentrations. In addition, mouse studies indicate that they provide broad tissue distribution and knockdown of the targeted protein in tumor xenografts. Together, these data demonstrate a protein knockdown system combining many of the favorable properties of small-molecule agents with the potent protein knockdown of RNAi and CRISPR.

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Section: Discussionmentioning

confidence: 99%

Catalytic in vivo protein knockdown by small-molecule PROTACs

et al. 2015

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“…On the basis that Fc-mediated phagocytosis enhances phagocytosis and killing of other intracellular pathogens, , we hypothesized that specific cell surface engineering of mycobacterial glycans with antibody-recruiting small molecules (ARMs) would enhance antibody-dependent phagocytosis by macrophages. ARMs are rationally designed to contain a pathogen-targeting motif and an antibody-recruiting motif, the latter of which is recognized by naturally occurring antibodies to trigger macrophage effector functions. − In order to overcome developing drug resistance, as well as immune evasion caused by natural variation in surface antigens, the selection of the pathogen-targeting motif can also be tailored to select essential surface molecules where mutations would be lethal. The ARM concept has previously been applied to create immunotherapy strategies for cancer, − viruses, fungi, and various types of bacteria, including Escherichia coli, Helicobacter pylori, Enterococcus faecium, and Staphylococcus aureus. − Here, we report proof-of-concept for the first mycobacterium-targeting ARM immunotherapy strategy.…”

Section: Introductionmentioning

confidence: 99%

Immune Targeting of Mycobacteria through Cell Surface Glycan Engineering

Dzigba,

Rylski,

Angera

et al. 2023

ACS Chem. Biol.

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Mycobacteria and other organisms in the order Mycobacteriales cause a range of significant human diseases, including tuberculosis, leprosy, diphtheria, Buruli ulcer, and non-tuberculous mycobacterial (NTM) disease. However, the intrinsic drug tolerance engendered by the mycobacterial cell envelope undermines conventional antibiotic treatment and contributes to acquired drug resistance. Motivated by the need to augment antibiotics with novel therapeutic approaches, we developed a strategy to specifically decorate mycobacterial cell surface glycans with antibody-recruiting molecules (ARMs), which flag bacteria for binding to human-endogenous antibodies that enhance macrophage effector functions. Mycobacterium-specific ARMs consisting of a trehalose targeting moiety and a dinitrophenyl hapten (Tre-DNPs) were synthesized and shown to specifically incorporate into outer-membrane glycolipids of Mycobacterium smegmatis via trehalose metabolism, enabling recruitment of anti-DNP antibodies to the mycobacterial cell surface. Phagocytosis of Tre-DNP-modified M. smegmatis by macrophages was significantly enhanced in the presence of anti-DNP antibodies, demonstrating proof-of-concept that our strategy can augment the host immune response. Because the metabolic pathways responsible for cell surface incorporation of Tre-DNPs are conserved in all Mycobacteriales organisms but absent from other bacteria and humans, the reported tools may be enlisted to interrogate host–pathogen interactions and develop immune-targeting strategies for diverse mycobacterial pathogens.

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Re‐engineering the Immune Response to Metastatic Cancer: Antibody‐Recruiting Small Molecules Targeting the Urokinase Receptor

et al. 2016

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Developing selective strategies to treat metastatic cancers remains a significant challenge. Herein, we report the first antibody-recruiting small molecule (ARM) that is capable of recognizing the urokinase-type plasminogen activator receptor (uPAR), a uniquely overexpressed cancer cellsurface marker, and facilitating the immune-mediated destruction of cancer cells. A co-crystal Correspondence to: David A. Spiegel. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201510866. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript structure of the ARM-U2/uPAR complex was obtained, representing the first crystal structure of uPAR complexed with a non-peptide ligand. Finally, we demonstrated that ARM-U2 substantially suppresses tumor growth in vivo with no evidence of weight loss, unlike the standard-of-care agent doxorubicin. This work underscores the promise of antibody-recruiting molecules as immunotherapeutics for treating cancer. Keywordsantitumor agents; cell recognition; drug design; immunology; medicinal chemistryTumor metastasis involves the invasion of cancer cells into surrounding tissues, a process often accelerated by cell-surface proteases. One such protease, the urokinase-type plasminogen activator (uPA), breaks down extracellular matrix proteins and activates migration-inducing signal cascades upon binding to the urokinase-type plasminogen activator receptor (uPAR). [1] Both uPA and uPAR expression are substantially upregulated in invasive cancer cells com-pared to healthy cells or benign tumors. [2] In clinical settings, uPAR levels have been shown to correlate with metastatic potential and poor clinical outcomes. [1a] As such, uPAR has gained recognition as a promising target for treating metastatic cancers from diverse tissues of origin, including breast, colon, stomach, and bladder. [3,4] Antibody-recruiting molecules (ARMs) are bifunctional molecules capable of delivering endogenous antibodies to disease-causing entities, leading to their destruction and/or clearance by the immune system. Our group and others have previously developed ARMs that target various cancers and infectious agents. These novel immunotherapies have the potential both to complement protein-based agents while overcoming their challenges, such as poor oral bioavailability, high molecular weights, and immunogenicity. [5] Our group previously reported an ARM capable of targeting uPAR-expressing cancer cells for immune-mediated cell death. [5] Although effective in vitro, the reported con-struct (termed ARM-U1) contained the uPA protein at its target binding terminus (TBT), imparting many of the limitations of biologics. We therefore hypothesized that the therapeutic potential of this agent could be significantly improved upon by replacing the uPA protein with a highaffinity uPAR-binding small molecule (Figure 1 A).Herein, we report the design, synthesis, and in vitro and in vivo evaluation of a secondgeneration, low-molecular...

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A call to ARMs: the promise of immunomodulatory small molecules

Cited by 6 publications

References 19 publications

Catalytic in vivo protein knockdown by small-molecule PROTACs

Catalytic in vivo protein knockdown by small-molecule PROTACs

Immune Targeting of Mycobacteria through Cell Surface Glycan Engineering

Re‐engineering the Immune Response to Metastatic Cancer: Antibody‐Recruiting Small Molecules Targeting the Urokinase Receptor

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