New Novobiocin Analogues as Antiproliferative Agents in Breast Cancer Cells and Potential Inhibitors of Heat Shock Protein 90

Abstract

Selective hsp90 inhibitors simultaneously destabilize and deplete key signaling proteins involved in cell proliferation and survival, angiogenesis, and metastasis. Investigation of novobiocin analogues lacking the noviose moiety as novel inhibitors of hsp90 was carried out. A novel series of 3-aminocoumarin analogues has been produced and screened in cell proliferation, and the molecular signature of hsp90 inhibition was assessed by depletion of estrogen receptor, HER2, Raf-1, and cdk4 in human breast cancer cells. This structure-activity relationship study highlights the crucial role of the C-4 and/or C-7 positions of coumarin which appeared to be essential for degradation of hsp90 client proteins. Removal of the noviose moiety in novobiocin together with introduction of a tosyl substituent at C-4 or C-7 coumarins provides 6e and 6f as lead structures which compared favorably with novobiocin as demonstrated by enhanced rates of cell death. The processing and activation of caspases 7 and 8 and the subsequent cleavage of PARP by 6e suggest stimulation of the extrinsic apoptosis pathway.

KU135, a Novel Novobiocin-Derived C-Terminal Inhibitor of the 90-kDa Heat Shock Protein, Exerts Potent Antiproliferative Effects in Human Leukemic Cells

“…However, the potential clinical utility of several of the N-terminal inhibitors as anticancer drugs has been dampened significantly due to concerns about their adverse hepatotoxic effects (Egorin et al, 1998) and tendency to induce expression of cytoprotective Hsp90 and Hsp70 proteins (Chiosis et al, 2003;Whitesell et al, 2003;Powers and Workman, 2007;Schmitt et al, 2007). More recently, the observation was made that Hsp90 contains a previously unrecognized C-terminal ATP-binding domain (Marcu et al, 2000a,b), which has led several groups to pursue the development of specific C-terminal Hsp90 inhibitors as potential anticancer drug modalities (Burlison et al, 2006Le Bras et al, 2007;Donnelly et al, 2008;Radanyi et al, 2009). Both N-terminal and C-terminal Hsp90 inhibitors can exert an antiproliferative response, in some instances, by stimulating apoptosis (Isaacs et al, 2003;Georgakis and Younes, 2005;Whitesell and Lindquist, 2005), although the underlying mechanisms are not well understood.…”

Crystal structure of 3-[(2,2-dimethylchroman-6-yl)carbonylamino]-7-hydroxy- 8-methyl-2-oxo-2H-chromen-4-yl toluene-4-sulfonate, C29H27NO8S

“…Unfortunately, the ability of novobiocin to induce degradation of hsp90 clientproteins is relatively weak and requires further investigation. In an effort to identify more potent inhibitors of hsp90, asmall library of novobiocin analogues lackingthe noviose moiety was synthesized [5] and initial structure-activity relationships (SAR) revealed that removal of the noviose moiety in novobiocin together with introduction of atosyl substituent at C-4 coumarin derivatives provide the title compoundasalead structure which compared favorably with the parent novobiocin as demonstrated by enhanced ratesofcell death. The title compound is an amide having a3-amino-4-hydroxy-7-p-toluene sulfonate-8-methyl coumarin (A) and 3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carboxylic acid (B).…”

HER2/neu: an increasingly important therapeutic target. Part 1: basic biology & therapeutic armamentarium

“…The diverse activities and clients of HSP90 result in a number of biological pathways being impacted by HSP90 inhibition [47], several of which involve, directly or indirectly, the HER2/neu signaling pathways. Thus, it is not surprising that a substantial effort is being put forth by numerous groups and companies to develop HSP90 inhibitors with attractive therapeutic to toxicity ratios and pharmacokinetics [293][294][295][296][297][298][299][300][301][302][303][304]. One of the more impor-future science group HER2/neu: an increasingly important therapeutic target.…”