857402-23-4

Basic information

• Product Name: Retaspimycin
• Synonyms: retaspimycin;18,21-Didehydro-17-demethoxy-18,21-dideoxo-18,21-dihydroxy-17-(2-propenylamino)geldanamycin;Unii-bzf2zm0I5z
• CAS NO: 857402-23-4
• Molecular Formula: C₃₁H₄₅N₃O₈
• Molecular Weight: 587.7
• Mol File: 857402-23-4.mol
• Article Data: 6

Chemical Properties

• Boiling Point: 800.9±65.0 °C(Predicted)
• Appearance: /
• Density: 1.23
• Solubility: Soluble in DMSO
• PKA: 10.15±0.70(Predicted)
• CAS DataBase Reference: Retaspimycin(CAS DataBase Reference)
• NIST Chemistry Reference: Retaspimycin(857402-23-4)
• EPA Substance Registry System: Retaspimycin(857402-23-4)

Safety Data

• Hazardous Substances Data: 857402-23-4(Hazardous Substances Data)

Usage

Description

Retaspimycin, also known as IPI-504, is a semi-synthetic ansamycin derivative and a small-molecule inhibitor of heat shock protein 90 (HSP90) with antiproliferative and antineoplastic activities. It is a hydroquinone-reduced form of tanespimycin and a semi-synthetic analogue of geldanamycin, typically used in cancer treatment as the hydrochloride salt.
Used in Pharmaceutical Industry:
Retaspimycin is used as an anticancer agent for its ability to bind to and inhibit the cytosolic chaperone functions of HSP90. This action maintains the stability and functional shape of many oncogenic signaling proteins, which may be overexpressed or overactive in tumor cells. Retaspimycin-mediated inhibition of HSP90 promotes the proteasomal degradation of oncogenic signaling proteins in susceptible tumor cell populations, potentially inducing apoptosis.
Orphan drug designation was assigned to Retaspimycin by the FDA for the treatment of gastrointestinal stromal cancer (GIST). However, it is important to note that Infinity Pharmaceuticals has discontinued the development of Retaspimycin (IPI-504) due to lack of efficacy in 2013.

Biological Activity

IPI-504 potently inhibits proliferation in several tumor cell lines with 50% inhibition concentration IC50 values ranging from 10-40 nM and has been used for the treatment of gastrointestinal stromal tumors, soft-tissue sarcomas and non-small cell lung cancer.

Mode of action

Cancer cells depend on the Hsp90 chaperone to maintain many proteins critical for cancer growth, proliferation and survival in a functional state. Retaspimycin binds to and inhibits the cytosolic chaperone functions of HSP90, which maintains the stability and functional shape of many oncogenic signaling proteins and may be overexpressed or overactive in tumor cells. Retaspimycin-mediated inhibition of HSP90 promotes the proteasomal degradation of oncogenic signaling proteins in susceptible tumor cell populations, which results in the induction of apoptosis.

references

[1]. hanson b e, vesole d h. retaspimycin hydrochloride (ipi-504): a novel heat shock protein inhibitor as an anticancer agent. 2009.[2]. floris g, debiec-rychter m, wozniak a, et al. the heat shock protein 90 inhibitor ipi-504 induces kit degradation, tumor shrinkage, and cell proliferation arrest in xenograft models of gastrointestinal stromal tumors. molecular cancer therapeutics, 2011, 10(10): 1897-1908.

Upstream product

• 75747-14-7 17-allylamino-17-demethoxygeldanamycin 

Relevant articles and documents

A mechanistic and structural analysis of the inhibition of the 90-kDa heat shock protein by the benzoquinone and hydroquinone ansamycins

The benzoquinone ansamycins inhibit the ATPase activity of the 90-kDa heat shock protein (Hsp90), disrupting the function of numerous client proteins involved in oncogenesis. In this study, we examine the role of NAD(P)H:quinone oxidoreductase 1 (NQO1) in the metabolism of trans-and cis-amide isomers of the benzoquinone ansamycins and their mechanism of Hsp90 inhibition. Inhibition of purified human Hsp90 by a series of benzoquinone ansamycins was examined in the presence and absence of NQO1, and their relative rate of NQO1-mediated reduction was determined. Computational-based molecular docking simulations indicated that the trans-but not the cis-amide isomers of the benzoquinone ansamycins could be accommodated by the NQO1 active site, and the ranking order of binding energies correlated with the relative reduction rate using purified human NQO1. The trans-cis isomerization of the benzoquinone ansamycins in Hsp90 inhibition has been disputed in recent reports. Previous computational studies have used the closed or cocrystallized Hsp90 structures in an attempt to explore this isomerization step; however, we have successfully docked both the trans-and cis-amide isomers of the benzoquinone ansamycins into the open Hsp90 structure. The results of these studies indicate that both trans-and cisamide isomers of the hydroquinone ansamycins exhibited increased binding affinity for Hsp90 relative to their parent quinones. Our data support a mechanism in which trans-rather than cis-amide forms of benzoquinone ansamycins are metabolized by NQO1 to hydroquinone ansamycins and that Hsp90-mediated trans-cis isomerization via tautomerization plays an important role in subsequent Hsp90 inhibition. Copyright

ANSAMYCIN FORMULATIONS AND METHODS OF USE THEREOF

The present invention provides pharmaceutical compositions of reduced forms of benzoquinone-containing ansamycins, and salts thereof. The present invention also relates to the use of said pharmaceutical compositions in methods of treating and modulating disorders associated with hyperproliferation, such as cancer.

GELDANAMYCIN AND DERIVATIVES INHIBIT CANCER INVASION AND IDENTIFY NOVEL TARGETS

Geldanamycin derivatives that block the uPA-plasmin network and inhibit growth and invasion by glioblastoma cells and other tumors at femtomolar concentrations are potentially highly active anti-cancer drugs. GA and various 17-amino-17-demethoxygelddanamycin derivatives are disclosed that block HGF/SF-mediated Met tyrosine kinase receptor-dependent uPA activation at fM levels. Other ansamycins (macbecins I and II), GA derivatives, and radicicol required concentrations several logs higher (≥nM) to achieve such inhibition. The inhibitory activity of tested compounds was discordant with the known ability of drugs of this class to bind to hsp90, indicating the existence of a novel target(s) for HGF/SF -mediated events in tumor development. Methods of using such compounds to inhibit cancer cell activities and to treat tumors are disclosed. Such treatment with low doses of these highly active compounds provide an option for treating various Met-expressing tumors, in particular invasive brain cancers, either alone or in combination with conventional surgery, chemotherapy, or radiotherapy.