Heat shock protein (Hsp) 90 is an ATP-dependent molecular chaperone exploited by malignant cells to support activated oncoproteins, including many cancer-associated kinases and transcription factors, and is essential for oncogenic transformation. Originally viewed with skepticism, Hsp90 inhibitors are now actively pursued by the pharmaceutical industry, with 17 agents having entered clinical trials. Hsp90’s druggability was established using the natural products geldanamycin and radicicol which mimic the unusual ATP structure adopted in the chaperone’s N-terminal nucleotide-binding pocket and cause potent and selective blockade of ATP binding/hydrolysis, inhibit chaperone function, deplete oncogenic clients, and demonstrate antitumor activity. Preclinical data with these natural products have heightened interest in Hsp90 as a drug target, and 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) has demonstrated clinical activity (as defined by RECIST criteria) in HER2+ breast cancer. Many optimized synthetic small molecule Hsp90 inhibitors from diverse chemotypes are now in clinical trials. We review the discovery and development of Hsp90 inhibitors and assess their future potential. There has been significant learning from experience in both the basic biology and the translational drug development around Hsp90, enhanced by the use of Hsp90 inhibitors as chemical probes. Success will likely lie in treating cancers addicted to particular driver oncogene products, such as HER2, ALK, EGFR and BRAF, that are sensitive Hsp90 clients, as well as in malignancies, especially multiple myeloma, where buffering of proteotoxic stress is critical for survival. We discuss approaches to enhancing the effectiveness of Hsp90 inhibitors and highlight new chaperone and stress response pathway targets, including HSF1 and Hsp70.

https://clincancerres.aacrjournals.org/content/clincanres/18/1/64.full.pdf

Hsp90 molecular chaperone inhibitors: are we there yet?

Aging is the main risk factor for many chronic degenerative diseases and cancer. Increased senescent cell burden in various tissues is a major contributor to aging and age-related diseases. Recently, a new class of drugs termed senolytics were demonstrated to extending healthspan, reducing frailty and improving stem cell function in multiple murine models of aging. To identify novel and more optimal senotherapeutic drugs and combinations, we established a senescence associated β-galactosidase assay as a screening platform to rapidly identify drugs that specifically affect senescent cells. We used primary Ercc1
 −/− murine embryonic fibroblasts with reduced DNA repair capacity, which senesce rapidly if grown at atmospheric oxygen. This platform was used to screen a small library of compounds that regulate autophagy, identifying two inhibitors of the HSP90 chaperone family as having significant senolytic activity in mouse and human cells. Treatment of Ercc1
 −/∆ mice, a mouse model of a human progeroid syndrome, with the HSP90 inhibitor 17-DMAG extended healthspan, delayed the onset of several age-related symptoms and reduced p16INK4a expression. These results demonstrate the utility of our screening platform to identify senotherapeutic agents as well as identified HSP90 inhibitors as a promising new class of senolytic drugs. The accumulation of senescent cells is thought to contribute to the age-associated decline in tissue function. Here, the authors identify HSP90 inhibitors as a new class of senolytic compounds in an in vitro screening and show that administration of a HSP90 inhibitor reduces age-related symptoms in progeroid mice.

/pdf/identification-of-hsp90-inhibitors-as-a-novel-class-of-47e2yddfym.pdf

Identification of HSP90 inhibitors as a novel class of senolytics

FcγRIIB is the only inhibitory Fc receptor for IgG, common genetic variants of which are associated with susceptibility to autoimmune disease but, also, with protection from severe malaria. Furthermore, understanding the function of FcγRIIB has important implications for the use of therapeutic antibodies.

/pdf/fcgriib-in-autoimmunity-and-infection-evolutionary-and-3id7qvmw6d.pdf

FcγRIIB in autoimmunity and infection: evolutionary and therapeutic implications

https://www.cell.com/cell-chemical-biology/pdf/S1074-5521(10)00198-5.pdf

Probing the Probes: Fitness Factors For Small Molecule Tools

The recent development of a consensus definition and proposed diagnostic criteria for anaphylaxis offers promise for research efforts and a better understanding of the epidemiology and pathogenesis of this enigmatic and life-threatening disease. This review examines basic principles and recent research advances in the mechanisms of mast cell signaling believed to underlie anaphylaxis. The unfolding complexity of mast cell signaling suggests that the system is sensitive to regulation by any of several individual signaling pathways and intermediates and that complementary pathways regulate mast cell activation by amplified signals. The signaling events underlying anaphylactic reactions have largely been identified through experiments in genetically modified mice and supported by biochemical studies of mast cells derived from these mice. These studies have revealed that signaling pathways exist to both upregulate and downregulate mast cell responses. In this review we will thus describe the key molecular players in these pathways in the context of anaphylaxis.

Mechanisms of mast cell signaling in anaphylaxis

Background A human Fcγ-Fce fusion protein (GE2) designed to inhibit FceRI signaling by coaggregating FceRI with the inhibitory receptor FcγRIIB has been shown to inhibit mast cell activation and block cutaneous anaphylaxis. A critical issue remained as to whether the mechanism of GE2 inhibition is competition for IgE binding or inhibitory signaling through FcγRIIB. Objective Our aim was to define the in vitro and in vivo mechanism of action of a mouse homolog of GE2 (mGE) and to assess the potential of human GE2 (hGE2) for therapeutic administration. Methods The in vitro activity of mGE on mediator release and signaling pathways was characterized in IgE-sensitized bone marrow–derived mast cells (BMMCs). The in vivo activity of mGE was examined in mouse passive cutaneous and passive systemic anaphylaxis models, and the therapeutic activity of hGE2 was evaluated in Ascaris suum –sensitized cynomolgus monkeys. Results mGE inhibited release of histamine and cytokines by BMMCs from wild-type mice but not by BMMCs from FcγRIIB-deficient mice. In mice mGE blocked IgE-dependent anaphylaxis mediated by mast cells with sustained efficacy. In BMMCs mGE decreased spleen tyrosine kinase and extracellular signal-regulated kinases 1/2 phosphorylation and induced FcγRIIB phosphorylation and the subsequent recruitment of SH2 domain–containing inositol polyphosphate 5′ phosphatase (SHIP) 1 and SH2 domain–containing protein tyrosine phosphatase (SHP) 1/2 phosphatases. When administered therapeutically, hGE2 protected sensitized monkeys from local anaphylaxis for 3 weeks. Conclusion mGE-mediated inhibition of mast cell activation is associated with inhibitory signaling through FcγRIIB that results from activation of SHIP-1 and SHP-1/2 phosphatases.

A mouse Fcγ-Fcε protein that inhibits mast cells through activation of FcγRIIB, SH2 domain–containing inositol phosphatase 1, and SH2 domain–containing protein tyrosine phosphatases

Corrections to Heat Shock Protein 90: Inhibitors in Clinical Trials [J. Med. Chem. 2010, 53. 3. DOI: 10.1021/jm9004708]

Corrections to Heat Shock Protein 90: Inhibitors in Clinical Trials

Production, Characterization, and Biodistribution Studies of a Novel Hinge Engineered Domain-Deleted CC49 Monoclonal Antibody

Novel Antibody Hinge Regions for Efficient Production of CH2 Domain-deleted Antibodies

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