Hsp90 inhibitors

Alvespimycin (17- Oncology HSP90 inhibitor Phase I (solid Kosan (NIH) 88, 884... 

Waza M, Adachi H, Katsuno M, Minamiyama M, Sang C, Tanaka E Inukai A, Doyu M, Sobue G (2005) 17-AAG an Hsp90 inhibitor, ameliorates poly glutamine-mediated motor neuron degeneration. Nat Med 11 1088-1095. 

Moulin E, Zoete V, Barluenga S, Karplus M, Winssinger N, Design, synthesis, and biological evaluation of HSP90 inhibitors based on conformational analysis of radicicol and its analogues, / Am Chem Soc 127 6999—7004, 2005. 

Initial attention in the development of Hsp90 inhibitors as anticancer agents was focused on two natural products, geldanamycin (compound 43, Fig. 8) and radicicol (also called monorden, compound 44, Fig. 8). These compounds bind into the ATP-binding cleft of the N-terminal domain of Hsp90 preventing the chaperone from cycling between its ADP and ATP-bound... 

Zsebik B, Citri A, Isola J et al (2006) Hsp90 inhibitor 17-AAG reduces ErbB2 levels and inhibits proliferation of the trastuzumab resistant breast tumor ceU Une JIMT-1. Immunol Lett 104 146-155... 

After validating the database they used the connectivity map to obtain new information they queried the database with expression signatures from patients and animal models to find small molecules that were already in the database that may mimic or suppress particular diseases. In subsequent studies, they identified geduin, an HSP90 inhibitor, as a new lead compound for the treatment of prostate cancer (59) and ra-pamycin as a potential useful drug for treatment of acute lymphocytic leukemia resistant to dexamethasone (60). 

Indeed, 17AAG, a derivative of GA, was the first-in-class Hsp90 inhibitor subjected to clinical trials in patients with hematological and solid tumors (Sausville, Tomaszewski, and Ivy 2003). 

A homogeneous and sensitive HTRF binding assay was developed to allow prosecution of an HTS campaign for novel small molecule Hsp90 inhibitors. The HTRF assay was based on a non-radio-active resonance energy transfer between a donor label (europium chelate) and an acceptor label (allophycocyanin [APC]) brought into close proximity by a specific binding interaction. 

Undoubtedly, potent and isoform-selective Hsp90 inhibitors will help elucidate the biology of each isoform and determine whether targeting one particular isoform may provide a better therapeutic window. 

Kamal, A. et al. 2003. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425, 407-410. 

Gyurkocza B, et al. Antileukemic activity of shepherdin and 112. molecular diversity of hsp90 inhibitors. J. Natl. Cancer Inst. 2006 98 1068-1077. 

George P, et al. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation 110. of FLT-3. Blood 2005 105 1768-1776. 

---