Structure−Immunosuppressive Activity Relationships of New Analogues of 15-Deoxyspergualin. 1. Structural Modifications of the Hydroxyglycine Moiety

Lebreton, Luc; Annat, Jocelyne; Derrepas, Philippe; Dutartre, Patrick; Renaut, Patrice

doi:10.1021/jm980431g

Cited by 48 publications

(37 citation statements)

References 30 publications

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“…An analysis of the resulting structure-activity relationship (SAR) suggested that the guanidylated alkyl group and hydroxyl amide core were necessary for bioactivity, confirming earlier findings [187,203]. In 1999, Renaut and co-workers increased the stability of the core hydroxyl amide against hydrolysis through the substitution of the hemiaminal group with a carbamate [201]. The resulting product, known as tresperimus (Fig.…”

Section: Spergualin: R = Oh (S)supporting

confidence: 65%

“…Factors limiting the utility of 15-DSG are the inherent instability of the molecule at varying pHs in vitro and its rapid metabolic degradation in vivo; 15-DSG also exhibits low oral bioavailability (<5%) [198,201]. Like the parent compound, spergualin, 15-DSG undergoes facile hydrolysis of the hydroxyamide moiety, with a half-life of 48 h at pH 7 and only 2 h at pH 10 (Scheme 1) [201].…”

Section: Spergualin: R = Oh (S)mentioning

confidence: 99%

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The Effect of Structure and Mechanism of the Hsp70 Chaperone on the Ability to Identify Chemical Modulators and Therapeutics

Manos-Turvey

Brodsky

Wipf

2015

Topics in Medicinal Chemistry

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The role of the Hsp70 molecular chaperone in effecting proper cellular protein folding, transport, and degradation processes, stabilizing protein complexes, and maintaining membrane integrity has long been recognized. More recently, Hsp70 has been linked to severe neurological diseases, such as Alzheimer's, Parkinson's and Huntington's disease, as well as to cystic fibrosis and cancer. As a result, there is a growing interest in the development of smallmolecule modulators of Hsp70 function. While several distinct classes of Hsp70 agonists and antagonists have been identified to date, clinical studies with Hsp70-targeted drugs have yet to be initiated, and proof of principle for therapeutic benefits remains to be established. However, a large body of preclinical biological evidence suggests that this chaperone plays a key role in many human diseases associated with protein (un)folding and trafficking and that the continued development of Hsp70 modulators will yield novel therapeutic strategies.

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Section: Spergualin: R = Oh (S)supporting

confidence: 65%

Section: Spergualin: R = Oh (S)mentioning

confidence: 99%

The Effect of Structure and Mechanism of the Hsp70 Chaperone on the Ability to Identify Chemical Modulators and Therapeutics

Manos-Turvey

Brodsky

Wipf

2015

Topics in Medicinal Chemistry

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“…6 Several analogs were obtained recently through organic synthesis. 7,8 One of these compounds, designated LF 15-0195, has demonstrated its efficacy in preventing graft-versus-host disease 8 and in treating collagen type II-induced arthritis 9,10 in mice models. Although LF 15-0195 is now tested in human clinics, the molecular mechanisms of its immunosuppressive activity differ from currently used immunosuppressive agents but remain poorly understood.…”

mentioning

confidence: 99%

LF 15-0195 immunosuppressive agent enhances activation-induced T-cell death by facilitating caspase-8 and caspase-10 activation at the DISC level

Ducoroy

Micheau

Perruche

et al. 2003

Blood

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The deoxyspergualin derivative LF 15-0195 has demonstrated some efficacy in animal models of autoimmune and graftversus-host diseases and is currently tested in clinics. The molecular mechanisms of LF 15-0195 immunosuppressive activity remained unknown. We show that exposure to LF 15-0195 sensitizes Jurkat T cells to apoptosis induced by an agonistic anti-CD95 antibody (CH11 clone) and by the cytokine TNF-related apoptosisinducing ligand. LF 15-0195 does not demonstrate any significant effect on the postmitochondrial activation of caspases, nor does it modify overall expression of CD95, Fas-associated death domain, and procaspase-8. The compound facilitates the recruitment of these molecules to the death-inducing signaling complex (DISC) and enhances caspase-8 and -10 activation, thus increasing cytochrome c and direct IAP binding with low pI (DIABLO)/ Smac mitochondrial release. LF 15-0195 also sensitizes Jurkat T cells to CD3-mediated apoptosis, an in vitro model for activation-induced T-cell death (AICD). LF 15-0195-mediated sensitization to AICD was further confirmed in human peripheral T cells exposed to anti-CD3 antibodies, then cultured in the presence of interleukin-2. In these cells, LF 15-0195 increased apoptosis triggered by either anti-CD95 antibodies or CD3 restimulation, whereas no effect was observed on "passive apoptosis." Finally, in bone marrow recipient mice, LF 15-0195 enhanced allogeneic donor T-cell death, which required a functional CD95 pathway. These results suggest that LF 15-0195 sensitizes T cells to AICD by increasing caspase activation at the DISC level in response to CD95 engagement. This original mechanism, together with LF 15-0195 efficacy in various disease models, makes this compound a promising immunosuppressive drug. Introduction 15-deoxyspergualin is an antibiotic that possesses both antitumor 1 and immunosuppressive 2 activities. This compound was shown to bind specifically to the constitutively expressed cytosolic heat shock protein (Hsp) Hsc70 as well as the Hsp90 family of proteins and to inhibit their ATPase activity. [3][4][5] Although it has proven effectiveness in the prevention and treatment of transplant rejection, the clinical use of 15-deoxyspergualin has been limited by its toxicity. 6 Several analogs were obtained recently through organic synthesis. 7,8 One of these compounds, designated LF 15-0195, has demonstrated its efficacy in preventing graft-versus-host disease 8 and in treating collagen type II-induced arthritis 9,10 in mice models. Although LF 15-0195 is now tested in human clinics, the molecular mechanisms of its immunosuppressive activity differ from currently used immunosuppressive agents but remain poorly understood.Mature peripheral T cells can be deleted by a so-called "passive apoptosis." 11 It occurs in T lymphocytes that are not sufficiently stimulated by growth factors. 12,13 T cells are also capable of undergoing a unique form of cell death called activation-induced cell death (AICD). [14][15][16][17] This cell death results from repeated an...

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“…Subsequent work showed that this molecule has anticancer and immunosuppressive activities [112][113][114]. Synthetic efforts have removed some of the metabolic liabilities of spergualin, including the hydroxyl at carbon 15, which have greatly improved the physical properties of the chemical series [115,116]. The most advanced of the spergualin analogs, 15-deoxyspergualin (15-DSG), is clinically approved in Japan for the treatment of acute allograft rejection, making this molecule the lone Hsp70 inhibitor approved for human use [117,118].…”

Section: Spergualinmentioning

confidence: 99%

Allosteric Inhibitors of Hsp70: Drugging the Second Chaperone of Tumorigenesis

Srinivasan

Shao

et al. 2015

Topics in Medicinal Chemistry

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Cancer cells survive in the presence of stresses that would normally cause cell death. To accomplish this feat, they express elevated levels of the molecular chaperones: heat shock protein 70 (Hsp70) and heat shock protein 90 (Hsp90). Knockdown of these chaperones is selectively toxic to cancer cells, suggesting that they might be promising nodes for anticancer therapy. However, while inhibitors of Hsp90 are well known, progress in the development of Hsp70 inhibitors has proven more difficult. Hsp70 binds tightly to ATP through a highly conserved domain of the actin/hexokinase superfamily, making it challenging to identify selective, competitive inhibitors. Despite this obstacle, progress has been made and first-generation molecules are being deployed. To supplement these efforts, compounds that target important allosteric sites on the chaperone have also been discovered. In some of these cases, the molecules have been shown to control key protein-protein interactions between Hsp70 and its co-chaperones. In other cases, allosteric sites have been used to gain unexpected selectivity for members of the Hsp70 family. Here, we review recent progress in the development of Hsp70 inhibitors.

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Structure−Immunosuppressive Activity Relationships of New Analogues of 15-Deoxyspergualin. 1. Structural Modifications of the Hydroxyglycine Moiety

Cited by 48 publications

References 30 publications

The Effect of Structure and Mechanism of the Hsp70 Chaperone on the Ability to Identify Chemical Modulators and Therapeutics

The Effect of Structure and Mechanism of the Hsp70 Chaperone on the Ability to Identify Chemical Modulators and Therapeutics

LF 15-0195 immunosuppressive agent enhances activation-induced T-cell death by facilitating caspase-8 and caspase-10 activation at the DISC level

Allosteric Inhibitors of Hsp70: Drugging the Second Chaperone of Tumorigenesis

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