Design of quinolinedione-Based geldanamycin analogues

Hargreaves, Robert H J; Whitesell, Luke; Skibo, Edward B.

doi:10.1016/s0960-894x(03)00650-4

Cited by 18 publications

(23 citation statements)

References 18 publications

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“…The most important Hsp90 inhibitors are geldanamycin ( Whitesell et al ., 1994 ), its less toxic analog, 17‐allylamino‐17‐demethoxy‐geldanamycin (17AAG) ( Schulte & Neckers, 1998 ) as well as radicicol, and its more stable oxime derivatives ( Soga et al ., 1998 ; Agatsuma et al ., 2002 ; Ikuina et al ., 2003 ), which have a higher affinity for Hsp90 than geldanamycin ( Roe et al ., 1999 ). Recently, new geldanamycin analogs ( Hargreaves et al ., 2003 ) as well as a third class of tumor‐specific Hsp90 inhibitors, the purine‐scaffold inhibitors, were developed ( Chiosis et al ., 2002 ; Vilenchik et al ., 2004 ), and there are ongoing efforts to synthesize even more Hsp90‐interacting drug candidates ( Banerji et al ., 2003 ; Maloney et al ., 2003 ; Workman, 2004 ; Dymock et al ., 2005 ; Kreusch et al ., 2005 ) (Table 1). Hsp90 inhibition was achieved in an unusual way, using the antitumor agent histone deacetylase inhibitors.…”

Section: Therapeutic Potential Of Hsp90 Inhibitionmentioning

confidence: 99%

Heat shock proteins as emerging therapeutic targets

Sőti

Nagy

Giricz

et al. 2005

British J Pharmacology

344

251

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Chaperones (stress proteins) are essential proteins to help the formation and maintenance of the proper conformation of other proteins and to promote cell survival after a large variety of environmental stresses. Therefore, normal chaperone function is a key factor for endogenous stress adaptation of several tissues. However, altered chaperone function has been associated with the development of several diseases; therefore, modulators of chaperone activities became a new and emerging field of drug development. Inhibition of the 90 kDa heat shock protein (Hsp)90 recently emerged as a very promising tool to combat various forms of cancer. On the other hand, the induction of the 70 kDa Hsp70 has been proved to be an efficient help in the recovery from a large number of diseases, such as, for example, ischemic heart disease, diabetes and neurodegeneration. Development of membrane-interacting drugs to modify specific membrane domains, thereby modulating heat shock response, may be of considerable therapeutic benefit as well. In this review, we give an overview of the therapeutic approaches and list some of the key questions of drug development in this novel and promising therapeutic approach.

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Section: Therapeutic Potential Of Hsp90 Inhibitionmentioning

confidence: 99%

Heat shock proteins as emerging therapeutic targets

Sőti

Nagy

Giricz

et al. 2005

British J Pharmacology

344

251

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“…A number of attempts have been made to generate inhibitors of Hsp90 with increased selectivity towards ErbB-2, as this is expected to reduce the toxicity potentially associated with inhibition of an essential, ubiquitous protein such as Hsp90. These approaches include formation of GA dimers, 135 as well as ErbB-2-directed antibody-conjugates of GA. 136 In addition, different approaches are being taken in an effort to produce additional classes of Hsp90 inhibitory drugs [137][138][139][140] (for a review see ref. 141).…”

Section: Interference With the Activity Of Hsp90 As A Therapeutic Modmentioning

confidence: 99%

The Achilles Heel of ErbB-2/HER2: Regulation by the Hsp90 Chaperone Machine and Potential for Pharmacological Intervention

Citri¹,

Kochupurakkal²,

Yarden³

2004

Cell Cycle

153

111

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© 2 0 0 3 L a n d e s B i o s c i e n c e . N o t f o r D i s t r i b u t i o n ABSTRACTSignal transduction mediated by ErbB/HER receptor tyrosine kinases is crucial for the development and maintenance of epithelial tissues, and aberrant signaling is frequently associated with malignancies of epithelial origin. This review focuses on the roles played by the Hsp90 chaperone machinery in the regulation of signaling through the ErbB/HER network, and discusses potential therapeutic strategies that disrupt chaperone functions. Hsp90 and its associated cochaperones regulate ErbB signal transduction through multiple mechanisms. The chaperone system controls the stability of the nascent forms of both ErbB-1 (EGF-receptor) and ErbB-2/HER2, while regulation of the mature form is restricted to ErbB-2. Regulation by the Hsp90 complex extends to downstream effectors of ErbB signaling, namely Raf-1, Pdk-1 and Akt/PKB. Disrupting the function of Hsp90 results in the degradation of both the receptors and their effectors, thereby inhibiting tumor cell growth. The importance of an Hsp90-recognition motif located within the kinase domain of ErbB-2 is discussed, as well as a direct role for Hsp90 in regulating tyrosine kinase activity. In light of recent observations, we emphasize the ability of specific tyrosine kinase inhibitors to selectively target ErbB-2 to the chaperone-mediated degradation pathway. ErbB-specific drugs are already used to treat cancers, and clinical trials are underway for additional compounds that intercept ErbB signaling, including drugs that target Hsp90. Hence, the dependence of ErbB-2 upon Hsp90 reveals an Achilles heel, which opens a window of opportunity for combating cancers driven by the ErbB/HER signaling network.

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“…7-Acetamido-2-methyl-quinoline-5,8dione (1) and 6-acetamido-2-methyl-quinoline-5,8-dione (2) were synthesized according to the literature methods [19,20]. The reactions of Re(CO) 5 Cl with 7-acetamido-2-methyl-quinoline-5,8-dione and 6-acetamido-2-methyl-quinoline-5,8-dione were performed under an argon atmosphere.…”

Section: General Proceduresmentioning

confidence: 99%

“…The complexes 3$CHCl 3 and 4$CHCl 3 were prepared by refluxing of [Re (CO) 5 Cl] with a small excess of 7-acetamido-2-methyl-quinoli ne-5,8-dione and 6-acetamido-2-methyl-quinoline-5,8-dione in (4) 119.2(2) C(5)eC(4)eC (3) 116.6(3) C(5)eC(4)eC (9) 121.0(2) C(3)eC(4)eC (9) 122.5(2) O(3)eC(11)eN (2) 120.9(2) O(3)eC(11)eC (12) 124.0(2) Fig. 3.…”

Section: Preparation and Infrared Datamentioning

confidence: 99%