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Ansamycin

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David Ross – 1st expert on this subject based on the ideXlab platform

  • Abstract 1788: 19-Substituted benzoquinone Ansamycins. Hsp90 inhibitors with decreased off-target toxicity
    Cancer Research, 2014
    Co-Authors: Chuan-hsin Chang, David Siegel, Derek A. Drechsel, Russell R. A. Kitson, Donald S. Backos, Cynthia Ju, Christopher J. Moody, David Ross

    Abstract:

    Benzoquinone Ansamycin (BQA) Hsp90 inhibitors such as 17-DMAG and 17-AAG have off-target toxicities in clinical trials including hepatotoxicity. Mechanisms underlying the toxicity of quinones are a function of their ability to redox cycle and/or arylate cellular nucleophiles at the unsubstituted 19-position of the molecule. Therefore, we designed 19-substituted BQAs to prevent glutathione conjugation and non-specific interactions with protein thiols as an approach to reduce the hepatotoxicity and minimize off-target effects of the BQA class of Hsp90 inhibitors. In this study, the results showed that 19-substituted BQAs did not react with glutathione at the 19-position, while marked reactivity was observed using parent BQAs. Importantly, while parent 17-DMAG induced cell death in primary and cultured mouse hepatocytes, 19-phenyl and 19-methyl 17-DMAG showed reduced toxicity, validating the overall approach. There was no significant difference between the redox cycling ability of either 19-phenyl or 19-methyl 17-DMAG with their parental BQAs in both mouse and human liver microsomes. Accordingly, this suggests that arylation reactions at the unsubstituted 19-position are predominantly responsible for hepatotoxicity. 19-substituted17-DMAG inhibited purified Hsp90 ATPase activity in an NQO1-dependent manner that demonstrated increased inhibitory efficacy of the hydroquinone Ansamycin relative to its parent quinone. In human breast cancer cells, 19-phenyl BQAs induced growth inhibition in an NQO1-dependent manner with molecular signatures of Hsp90 inhibition, including decreases in client proteins and compensatory induction of Hsp70. These data indicate that 19-substituted BQAs may be useful Hsp90 inhibitors with decreased off target toxicity (Supported by NCI grant CA51210) Citation Format: Chuan-Hsin Chang, Derek A. Drechsel, Russell R.A. Kitson, David Siegel, Qiang You, Donald S. Backos, Cynthia Ju, Christopher J. Moody, David Ross. 19-Substituted benzoquinone Ansamycins. Hsp90 inhibitors with decreased off-target toxicity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1788. doi:10.1158/1538-7445.AM2014-1788

  • 19 substituted benzoquinone Ansamycin heat shock protein 90 inhibitors biological activity and decreased off target toxicity
    Molecular Pharmacology, 2014
    Co-Authors: Chuan-hsin Chang, David Siegel, Derek A. Drechsel, Russell R. A. Kitson, Donald S. Backos, Christopher J. Moody, Changqing Ju, David Ross

    Abstract:

    The benzoquinone Ansamycins (BQAs) are a valuable class of antitumor agents that serve as inhibitors of heat shock protein (Hsp)-90. However, clinical use of BQAs has resulted in off-target toxicities, including concerns of hepatotoxicity. Mechanisms underlying the toxicity of quinones include their ability to redox cycle and/or arylate cellular nucleophiles. We have therefore designed 19-substituted BQAs to prevent glutathione conjugation and nonspecific interactions with protein thiols to minimize off-target effects and reduce hepatotoxicity. 19-Phenyl– and 19-methyl–substituted versions of geldanamycin and its derivatives, 17-allylamino-17-demethoxygeldanamycin and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), did not react with glutathione, whereas marked reactivity was observed using parent BQAs. Importantly, although 17-DMAG induced cell death in primary and cultured mouse hepatocytes, 19-phenyl and 19-methyl DMAG showed reduced toxicity, validating the overall approach. Furthermore, our data suggest that arylation reactions, rather than redox cycling, are a major mechanism contributing to BQA hepatotoxicity. 19-Phenyl BQAs inhibited purified Hsp90 in a NAD(P)H:quinone oxidoreductase 1 (NQO1)–dependent manner, demonstrating increased efficacy of the hydroquinone Ansamycin relative to its parent quinone. Molecular modeling supported increased stability of the hydroquinone form of 19-phenyl-DMAG in the active site of human Hsp90. In human breast cancer cells, 19-phenyl BQAs induced growth inhibition also dependent upon metabolism via NQO1 with decreased expression of client proteins and compensatory induction of Hsp70. These data demonstrate that 19-substituted BQAs are unreactive with thiols, display reduced hepatotoxicity, and retain Hsp90 and growth-inhibitory activity in human breast cancer cells, although with diminished potency relative to parent BQAs.

  • Abstract 2769: The development of 19-substituted benzoquinone Ansamycins as potential anticancer drugs
    Cancer Research, 2012
    Co-Authors: Chuan-hsin Chang, David Siegel, Russell R. A. Kitson, Christopher J. Moody, David Ross

    Abstract:

    Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL

    Benzoquinone Ansamycins (BQA’s) were the first class of Hsp90 inhibitors developed but the use of the prototype agent geldanamycin was limited by hepatotoxicity. One major mechanism of toxicity of the BQA class is manifested via the electrophilic properties of the quinone and alkylation of cellular nucleophiles at the 19-position. We developed novel 19-substituted BQA’s in the geldanamycin (GA), 17-AAG and 17-DMAG series as a means to prevent arylation of cellular nucleophiles. 19-substituted BQA’s inhibited recombinant Hsp90 and did not react with thiols at the 19-position while marked thiol reactivity could be detected using their parent quinones. We examined the effects of different substitution patterns at the 19-position on the ability of BQAs to inhibit Hsp90 and induce growth inhibitory effects in breast cancer cell lines. We found that both 19-phenyl and 19-methyl BQA’s in the 17-AAG, 17-DMAG and GA series were effective inhibitors of purified Hsp90 as demonstrated using an ATPase assay particularly in the presence of NQO1 to generate the hydroquinone Ansamycin. Only 19-phenyl substituted BQAs were effective growth inhibitory agents in breast cancer cell lines using an MTT assay while 19-methyl substituted BQAs in the GA, 17-AAG and 17-DMAG series demonstrated only modest growth inhibition. The growth inhibitory effects of 19-phenyl BQAs were potentiated in cells containing high NQO1. Notably, 19-phenyl DMAG had similar growth inhibitory and apoptotic effects as its parent quinone, DMAG. These data demonstrate that the 19-phenyl BQAs had marked growth inhibitory, apoptotic, and client protein expression effect in breast cancer cells compared to 19-methyl BQAs (Supported by CA 51210).

    Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2769. doi:1538-7445.AM2012-2769

Chunhua Lu – 2nd expert on this subject based on the ideXlab platform

  • targeted discovery of pentaketide Ansamycin aminoAnsamycinsa g
    Organic Letters, 2019
    Co-Authors: Zishen Wang, Chunhua Lu, Yaoyao Li, Haoxin Wang, Yuemao Shen

    Abstract:

    Ansamycins are a class of macrolactams with diverse bioactivities, characterized by the unique 3-amino-5-hydroxybenzoic acid moiety. In this study, the Ansamycin gene cluster aas in Streptomyces sp. S35 was activated by the constitutive coexpression of two pathway-specific regulator genes aas1 and aas10, and seven novel pentaketide Ansamycin aminoAnsamycins A–G (1–7) were identified. Compound 4 with better antiproliferative activity indicated that the anthranilate analogues are probably promising building blocks for the production of unnatural Ansamycins with improved activity.

  • Targeted Discovery of Pentaketide Ansamycin AminoAnsamycinsA–G
    Organic Letters, 2019
    Co-Authors: Zishen Wang, Chunhua Lu, Yaoyao Li, Haoxin Wang, Yuemao Shen

    Abstract:

    Ansamycins are a class of macrolactams with diverse bioactivities, characterized by the unique 3-amino-5-hydroxybenzoic acid moiety. In this study, the Ansamycin gene cluster aas in Streptomyces sp. S35 was activated by the constitutive coexpression of two pathway-specific regulator genes aas1 and aas10, and seven novel pentaketide Ansamycin aminoAnsamycins A–G (1–7) were identified. Compound 4 with better antiproliferative activity indicated that the anthranilate analogues are probably promising building blocks for the production of unnatural Ansamycins with improved activity.

  • pentaketide Ansamycin microAnsamycins a i from micromonospora sp reveal diverse post pks modifications
    Organic Letters, 2018
    Co-Authors: Jianxiong Wang, Haoxin Wang, Wen Li, Chunhua Lu

    Abstract:

    Overexpression of the pathway-specific positive regulator gene mas13 activated the cryptic gene cluster mas, resulting in the isolation of nine novel pentaketide Ansamycins, namely, microAnsamycins A–I (1–9). These results not only revealed a biosynthetic gene cluster of pentaketide Ansamycins for the first time but also presented an unprecedented scenario of diverse post-PKS modifications in Ansamycin biosynthesis.

David Siegel – 3rd expert on this subject based on the ideXlab platform

  • Abstract 1788: 19-Substituted benzoquinone Ansamycins. Hsp90 inhibitors with decreased off-target toxicity
    Cancer Research, 2014
    Co-Authors: Chuan-hsin Chang, David Siegel, Derek A. Drechsel, Russell R. A. Kitson, Donald S. Backos, Cynthia Ju, Christopher J. Moody, David Ross

    Abstract:

    Benzoquinone Ansamycin (BQA) Hsp90 inhibitors such as 17-DMAG and 17-AAG have off-target toxicities in clinical trials including hepatotoxicity. Mechanisms underlying the toxicity of quinones are a function of their ability to redox cycle and/or arylate cellular nucleophiles at the unsubstituted 19-position of the molecule. Therefore, we designed 19-substituted BQAs to prevent glutathione conjugation and non-specific interactions with protein thiols as an approach to reduce the hepatotoxicity and minimize off-target effects of the BQA class of Hsp90 inhibitors. In this study, the results showed that 19-substituted BQAs did not react with glutathione at the 19-position, while marked reactivity was observed using parent BQAs. Importantly, while parent 17-DMAG induced cell death in primary and cultured mouse hepatocytes, 19-phenyl and 19-methyl 17-DMAG showed reduced toxicity, validating the overall approach. There was no significant difference between the redox cycling ability of either 19-phenyl or 19-methyl 17-DMAG with their parental BQAs in both mouse and human liver microsomes. Accordingly, this suggests that arylation reactions at the unsubstituted 19-position are predominantly responsible for hepatotoxicity. 19-substituted17-DMAG inhibited purified Hsp90 ATPase activity in an NQO1-dependent manner that demonstrated increased inhibitory efficacy of the hydroquinone Ansamycin relative to its parent quinone. In human breast cancer cells, 19-phenyl BQAs induced growth inhibition in an NQO1-dependent manner with molecular signatures of Hsp90 inhibition, including decreases in client proteins and compensatory induction of Hsp70. These data indicate that 19-substituted BQAs may be useful Hsp90 inhibitors with decreased off target toxicity (Supported by NCI grant CA51210) Citation Format: Chuan-Hsin Chang, Derek A. Drechsel, Russell R.A. Kitson, David Siegel, Qiang You, Donald S. Backos, Cynthia Ju, Christopher J. Moody, David Ross. 19-Substituted benzoquinone Ansamycins. Hsp90 inhibitors with decreased off-target toxicity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1788. doi:10.1158/1538-7445.AM2014-1788

  • 19 substituted benzoquinone Ansamycin heat shock protein 90 inhibitors biological activity and decreased off target toxicity
    Molecular Pharmacology, 2014
    Co-Authors: Chuan-hsin Chang, David Siegel, Derek A. Drechsel, Russell R. A. Kitson, Donald S. Backos, Christopher J. Moody, Changqing Ju, David Ross

    Abstract:

    The benzoquinone Ansamycins (BQAs) are a valuable class of antitumor agents that serve as inhibitors of heat shock protein (Hsp)-90. However, clinical use of BQAs has resulted in off-target toxicities, including concerns of hepatotoxicity. Mechanisms underlying the toxicity of quinones include their ability to redox cycle and/or arylate cellular nucleophiles. We have therefore designed 19-substituted BQAs to prevent glutathione conjugation and nonspecific interactions with protein thiols to minimize off-target effects and reduce hepatotoxicity. 19-Phenyl– and 19-methyl–substituted versions of geldanamycin and its derivatives, 17-allylamino-17-demethoxygeldanamycin and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), did not react with glutathione, whereas marked reactivity was observed using parent BQAs. Importantly, although 17-DMAG induced cell death in primary and cultured mouse hepatocytes, 19-phenyl and 19-methyl DMAG showed reduced toxicity, validating the overall approach. Furthermore, our data suggest that arylation reactions, rather than redox cycling, are a major mechanism contributing to BQA hepatotoxicity. 19-Phenyl BQAs inhibited purified Hsp90 in a NAD(P)H:quinone oxidoreductase 1 (NQO1)–dependent manner, demonstrating increased efficacy of the hydroquinone Ansamycin relative to its parent quinone. Molecular modeling supported increased stability of the hydroquinone form of 19-phenyl-DMAG in the active site of human Hsp90. In human breast cancer cells, 19-phenyl BQAs induced growth inhibition also dependent upon metabolism via NQO1 with decreased expression of client proteins and compensatory induction of Hsp70. These data demonstrate that 19-substituted BQAs are unreactive with thiols, display reduced hepatotoxicity, and retain Hsp90 and growth-inhibitory activity in human breast cancer cells, although with diminished potency relative to parent BQAs.

  • Abstract 2769: The development of 19-substituted benzoquinone Ansamycins as potential anticancer drugs
    Cancer Research, 2012
    Co-Authors: Chuan-hsin Chang, David Siegel, Russell R. A. Kitson, Christopher J. Moody, David Ross

    Abstract:

    Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL

    Benzoquinone Ansamycins (BQA’s) were the first class of Hsp90 inhibitors developed but the use of the prototype agent geldanamycin was limited by hepatotoxicity. One major mechanism of toxicity of the BQA class is manifested via the electrophilic properties of the quinone and alkylation of cellular nucleophiles at the 19-position. We developed novel 19-substituted BQA’s in the geldanamycin (GA), 17-AAG and 17-DMAG series as a means to prevent arylation of cellular nucleophiles. 19-substituted BQA’s inhibited recombinant Hsp90 and did not react with thiols at the 19-position while marked thiol reactivity could be detected using their parent quinones. We examined the effects of different substitution patterns at the 19-position on the ability of BQAs to inhibit Hsp90 and induce growth inhibitory effects in breast cancer cell lines. We found that both 19-phenyl and 19-methyl BQA’s in the 17-AAG, 17-DMAG and GA series were effective inhibitors of purified Hsp90 as demonstrated using an ATPase assay particularly in the presence of NQO1 to generate the hydroquinone Ansamycin. Only 19-phenyl substituted BQAs were effective growth inhibitory agents in breast cancer cell lines using an MTT assay while 19-methyl substituted BQAs in the GA, 17-AAG and 17-DMAG series demonstrated only modest growth inhibition. The growth inhibitory effects of 19-phenyl BQAs were potentiated in cells containing high NQO1. Notably, 19-phenyl DMAG had similar growth inhibitory and apoptotic effects as its parent quinone, DMAG. These data demonstrate that the 19-phenyl BQAs had marked growth inhibitory, apoptotic, and client protein expression effect in breast cancer cells compared to 19-methyl BQAs (Supported by CA 51210).

    Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2769. doi:1538-7445.AM2012-2769