17-Allylamino-demethoxy geldanamycin (17-AAG) inhibits the chaperone association of heat shock protein 90 (hsp90) with the heat shock factor-1 (HSF-1), which induces the mRNA and protein levels of hsp70. Increased hsp70 levels inhibit death receptor and mitochondria-initiated signaling for apoptosis. Here, we show that ectopic overexpression of hsp70 in human acute myelogenous leukemia HL-60 cells (HL-60/hsp70) and high endogenous hsp70 levels in Bcr-Abl-expressing cultured CML-BC K562 cells confers resistance to 17-AAG-induced apoptosis. In HL-60/hsp70 cells, hsp70 was bound to Bax, inhibited 17-AAG-mediated Bax conformation change and mitochondrial localization, thereby inhibiting the mitochondria-initiated events of apoptosis. Treatment with 17-AAG attenuated the levels of phospho-AKT, AKT, and c-Raf but increased hsp70 levels to a similar extent in the control HL-60/Neo and HL-60/hsp70 cells. Pretreatment with 17-AAG, which induced hsp70, inhibited 1-β-d-arabinofuranosylcytosine or etoposide-induced apoptosis in HL-60 cells. Stable transfection of a small interfering RNA (siRNA) to hsp70 completely abrogated the endogenous levels of hsp70 and blocked 17-AAG-mediated hsp70 induction, resulting in sensitizing K562/siRNA-hsp70 cells to 17-AAG-induced apoptosis. This was associated with decreased binding of Bax to hsp70 and increased 17-AAG-induced Bax conformation change. 17-AAG-mediated decline in the levels of AKT, c-Raf, and Bcr-Abl was similar in K562 and K562/siRNA-hsp70 cells. Cotreatment with KNK437, a benzylidine lactam inhibitor of hsp70 induction and thermotolerance, attenuated 17-AAG-mediated hsp70 induction and increased 17-AAG-induced apoptosis and loss of clonogenic survival of HL-60 cells. Collectively, these data indicate that induction of hsp70 attenuates the apoptotic effects of 17-AAG, and abrogation of hsp70 induction significantly enhances the antileukemia activity of 17-AAG.

https://cancerres.aacrjournals.org/content/canres/65/22/10536.full.pdf

Abrogation of Heat Shock Protein 70 Induction as a Strategy to Increase Antileukemia Activity of Heat Shock Protein 90 Inhibitor 17-Allylamino-Demethoxy Geldanamycin

Heat shock proteins are vital to cell survival under conditions of stress. They bind client proteins to assist in protein stabilization, translocation of polypeptides across cell membranes and recovery of proteins from aggregates. Heat shock protein inhibitors are a diverse group of novel agents that have been demonstrated to have pro-apoptotic effects on malignant cells through inhibition of ATP binding on the ATP/ADP-binding pocket of the heat shock protein. Initial development of heat shock protein 90 inhibitors, geldanamycin and 17-AAG, were limited by hepatotoxicity and the need for solvent carrying agents. In contrast, retaspimycin, or IPI-504, a derivative of geldanamycin and 17-AAG, is highly soluble in water and generally well tolerated. In Phase I/II trials, retaspimycin has shown activity in NSCLC and gastrointestinal stromal tumor. The most promising activity was observed in gastrointestinal stromal tumors. Phase I/II trials are currently underway to evaluate the dosing schedules and activity of IPI-504 in breast cancer. Given the in vitro activity in diffuse large B-cell lymphoma, mantle cell lymphoma, melanoma, leukemia and pancreatic cancer, current and future trials are of clinical interest. This article reviews IPI-504 and its utility in a wide variety of cancer phenotypes.

Retaspimycin hydrochloride (IPI-504): a novel heat shock protein inhibitor as an anticancer agent.

Provided herein, inter alia, are solid forms of geldanamycin analogs, pharmaceutical compositions comprising a geldanamycin analog and a crystallization inhibitor, methods of making and using such compositions. Additionally, provided are methods for the treatment of cancer, a neoplastic disease state and/or a hyperproliferative disorder, and methods of inhibiting Heat Shock Protein 90 (“Hsp90”).

Ansamycin formulations and methods of use thereof

Recent leaps in elucidating the biology of myeloma, particularly the intracellular pathways and the complex interaction with the bone marrow microenvironment, have resulted in an unprecedented surge of novel, targeted therapies and therapeutic regimens. There are currently over 30 new agents being tested in the treatment of multiple myeloma (MM). Many of these are novel, targeted agents that have demonstrated significant efficacy and prolonged survival. In this review, we summarize the current understanding of the mechanisms of action of novel therapies being tested in the preclinical and clinical settings in MM. These include agents that act directly on the intracellular signaling pathways, cell maintenance processes, and cell surface receptors. Finally, we present the clinical responses to some of these agents when used alone or in combination in clinical trials of patients with MM. Indeed, MM has become a model disease for the development of novel, therapeutic agents.

https://downloads.hindawi.com/journals/tswj/2006/353986.pdf

New frontiers in the treatment of multiple myeloma.

Aspects of the present invention provide compositions comprising a sulfur containing compound and a compound of the formula (I); and also provide methods of their preparation and use.

Ansamycin hydroquinone compositions

Anti-Tumor Activity of IPI-504, a Novel Hsp90 Inhibitor in Multiple Myeloma.

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Anti-Tumor Activity of IPI-504, a Novel Hsp90 Inhibitor in Multiple Myeloma.