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  • 1
    Online Resource
    Online Resource
    Abstract 1362: Discovery of a novel structural class of compounds: HLM-030376 and its analogs as potent chymotrypsin-like proteasome inhibitors
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 1362-1362
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 1362-1362
    Abstract: The ubiquitin-proteasome pathway plays a critical role in the regulated degradation of proteins involved in cell cycle control and tumor growth. Proteasome inhibitors cause selective apoptosis of malignant cells and represent a new class of antineoplastic agents. In 2003 Bortezomib (peptide boronate), a proteasome inhibitor was approved by FDA for treatment of multiple myeloma. Toxicity and tumor cell resistance against Bortezomib demand development of less toxic proteasome inhibitors with broader spectrum of tumor activity. Our aim is to develop non-peptidic small drug-like molecules as proteasome inhibitors. To this end, we have identified through in-house screening efforts HLM-030376 as a small molecule proteasome inhibitor with phenanthridine pharmacophore. HLM-030376 showed in-vitro chymotrypsin like, trypsin like and PGPH inhibitory activities with IC50 values 0.26, 0.19 and 2.07 µM respectively. Extensive synthetic modifications around the HLM-030376 pharmacophore were undertaken to aid the cell activity of this class of compounds. We will describe the synthesis and activity of analogs of HLM-030376 as potent proteasome inhibitors. The analogs of HLM-030376 showed in-vivo CT-L inhibitory activities (IC50 between 0.6-6.0 µM) against MDA-MB 468 breast cancer cell line as well as improved (IC50 between 70-200 nM) in-vitro CT-L inhibitory activities. The detailed in-vitro structure activity relationship (SAR) data of HLM-030376 and analogs will be discussed to understand the structural moieties responsible for proteasome activity. The whole cell activity data of HLM-030376 as well as in-silico docking studies will be presented as potential proteasome inhibitors for further development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1362. doi:10.1158/1538-7445.AM2011-1362
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-1362
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 2
    Online Resource
    Online Resource
    Discovery of PI-1840, a Novel Noncovalent and Rapidly Reversible Proteasome Inhibitor with Anti-tumor Activity
    Elsevier BV ; 2014
    In:  Journal of Biological Chemistry Vol. 289, No. 17 ( 2014-04), p. 11906-11915
    Details
    In: Journal of Biological Chemistry, Elsevier BV, Vol. 289, No. 17 ( 2014-04), p. 11906-11915
    Type of Medium: Online Resource
    ISSN: 0021-9258
    URL: Article
    DOI: 10.1074/jbc.M113.533950
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2014
    detail.hit.zdb_id: 2141744-1
    detail.hit.zdb_id: 1474604-9
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Abstract 1359: Identification of a novel class of compounds as proteasome inhibitors: Synthesis and structure activity relationship studies of PI-1833 library
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 1359-1359
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 1359-1359
    Abstract: The ATP-dependent ubiquitin-proteosome pathway is responsible for the controlled degradation of proteins in eukaryotic cells. The 26S proteosome is a multifunctional complex, consisting of a 19S regulatory particle (RP) and a 20S core particle (CP). The three main catalytic activities of the proteasome; peptidylglutamyl peptide hydrolysing (PGPH), trypsin-like (T-L), and chymotrypsin-like (CT-L), are mediated by three distinct catalytic β-1, β-2, and β-5 subunits, respectively. Owing to the central role of proteosome in maintaining homeostasis and hence its key position in many cellular processes, the development of inhibitors for CT-L activity has been the subject of considerable interest in the treatment of cancer. Selective inhibition of the CT-L activity of 20S proteasome represents a successful strategy in cancer therapy as demonstrated by Bortezomib (Velcade), a clinically approved drug for multiple myeloma and mantle lymphoma. Toxicity and tumor cell resistance against Bortezomib demand the development of improved and selective proteasome inhibitors. The potent proteasome inhibitors reported to date have been developed as aldehydes, boronates, vinylsulfones and expoxyketones and these compounds function through covalent modification of the N-terminal threonine residue of β-5 subunit. Small, drug-like synthetic proteasome inhibitors that are selective for cancer over normal cells are rare, but clearly would have a potential advantage over the existing inhibitors. PI-1833 was identified in our program as a ‘hit’ with in-vitro CT-L proteasome activity (IC50 = 0.58 μM). PI-1833 is a small molecule with oxadiazole pharmacophore and presents 3 points of diversity amenable for focused library synthesis. Lack of a reactive chemical moiety (or electrophilic moiety) to form proteasome adducts is an important feature of PI-1833. The first generation analogs of PI-1833 have shown promising SAR (in-vitro and in-vivo) toward proteasome inhibition with the IC50 values ranging from 0.3-0.7 μM. In this work we will present in-vitro and in-vivo structure activity relationship (SAR) data, synthesis and selectivity of a PI-1833 library and discuss the mode of proteasome inhibition (co-valent vs non co-valent) by this class of compounds. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1359. doi:10.1158/1538-7445.AM2011-1359
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-1359
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 4
    Online Resource
    Online Resource
    Oxadiazole-isopropylamides as Potent and Noncovalent Proteasome Inhibitors
    American Chemical Society (ACS) ; 2013
    In:  Journal of Medicinal Chemistry Vol. 56, No. 10 ( 2013-05-23), p. 3783-3805
    Details
    In: Journal of Medicinal Chemistry, American Chemical Society (ACS), Vol. 56, No. 10 ( 2013-05-23), p. 3783-3805
    Type of Medium: Online Resource
    ISSN: 0022-2623 , 1520-4804
    URL: Article
    DOI: 10.1021/jm400221d
    Language: English
    Publisher: American Chemical Society (ACS)
    Publication Date: 2013
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    SSG: 15,3
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  • 5
    Online Resource
    Online Resource
    Abstract 1810: PI-1840, a novel non-covalent and rapidly reversible proteasome inhibitor with anti-tumor activity
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 1810-1810
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 1810-1810
    Abstract: Non-covalent proteasome inhibitors that are less toxic and more effective against solid tumors than currently used proteasome inhibitors are desirable. Through HTS and hit-to-lead optimization efforts we have identified PI-1840, a potent and selective inhibitor for chymotrypsin-like (CT-L) (IC50 value = 27 ± 0.14 nM) over T-L and PGPH (IC50 values & gt;100 µM) activities of the proteasome. Furthermore, PI-1840 is over 100-fold more selective for the constitutive proteasome over the immunoproteasome. Dialysis and mass spectrometry studies demonstrate that PI-1840 is a non-covalent and rapidly reversible CT-L inhibitor. PI-1840 inhibits CT-L activity, induces the accumulation of proteasome substrates p27, Bax and IκB-α, inhibits survival pathways and proliferation, and induces apoptosis in human cancer cells. The mdm2/p53 disruptor, nutlin, sensitizes cancer cells to PI-1840 in a p53-dependent manner. Furthermore, the pan Bcl-2 antagonist BH3-M6 also sensitizes cancer cells to PI-1840. Finally, in vivo, PI-1840 but not Bortezomib (clinically used proteasome inhibitor) suppresses the growth in nude mice of human breast xenografts. These results warrant further evaluation of non-covalent and rapidly reversible proteasome inhibitor as potential anticancer agents against solid tumors. Citation Format: Said M. Sebti, Aslamuzzaman Kazi, Sevil Ozcan, Awet G. Tecleab, Ying Sun, Harshani Lawrence. PI-1840, a novel non-covalent and rapidly reversible proteasome inhibitor with anti-tumor activity. [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 1810. doi:10.1158/1538-7445.AM2014-1810
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-1810
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
    Online Resource
    Online Resource
    Abstract 2778: Development of non-covalent reversible proteasome inhibitors
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 2778-2778
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 2778-2778
    Abstract: Numerous cell cycle, apoptosis and angiogenesis-regulatory proteins undergo ubiquitin proteasome-dependent proteolysis. A proteasome inhibitor Velcade was approved for the treatment of multiple myeloma. However, Velcade is a covalent and slowly reversible inhibitor and is associated with undesired side effects. Non-covalent inhibitors with potentially less toxicity are desirable. In this abstract we report on a family of non-covalent inhibitors that resulted from our HTS screen of a 50,000 compound library against the chymotrypsin-like (CT-L) activity of purified 20S proteasome. Our initial hit PI-1833 (IC50 value = 0.5 uM) was used as a starting point for structure activity relationship studies that led to highly potent (IC50 value = 20 nM) and cell permeable derivatives. In addition to inhibiting CT-L in human breast cancer cells, these derivatives also induced the accumulation of two proteasome target proteins Bax and p27KIP, indicating their ability to inhibit proteasome activity in intact cells. Furthermore, these proteasome inhibitors also induced apoptosis and inhibited tumor cell growth. Further mechanistic studies as well as in vivo anti-tumor efficacy studies are ongoing. 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 2778. doi:1538-7445.AM2012-2778
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-2778
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
    Online Resource
    Online Resource
    Abstract 3894: Discovery, synthesis and SAR studies of a novel nonpeptidic reversible proteosome inhibitor with low nano-molar chymotrypsin like activity
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 3894-3894
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 3894-3894
    Abstract: The development of proteosome inhibitors for CT-L activity has been the subject of considerable interest in the treatment of cancer due to its critical role in maintaining homeostasis and hence its key position in many cellular processes. Proteosome inhibitors are classified as reversible or irreversible inhibitors according to their chemical structure and their mechanism of inhibition. Irreversible inhibitors possess a chemically reactive group, such as aldehydes, boronic acids, epoxy ketones that react with catalytic Thr1-O covalently, where as reversible inhibitors inhibit proteosome non-covalently via H-bond interactions (electrostatic and/or van der Waals). Bortezomib, a peptide boronic acid analog, is the first clinically approved proteosome inhibitor and is found to be an irreversible or slow reversible inhibitor that forms covalent bond with the N-terminal nucleophilic Thr1 in the β5 subunit of the proteasome. Reversible proteosome inhibitors (peptidic molecules) reported to date inhibit the proteosome non-covalently. Similar to Bortezomib, MLN9708 is a modified dipeptidyl boronic acid, which hydroylses immediately in plasma to MLN2238, is a potent, reversible and specific inhibitor of the chymotrypsin-like subunit of the proteasome. Small molecules as reversible proteosome inhibitors are less extensively investigated. In this study, we present the discovery of PI-184, non-peptidic small molecule with a pyridine and oxadiazole pharmacore as a reversible, potent and a novel proteasome inhibitor. Structure Activity relationship (SAR) guided synthesis of analogs around PI-184 led to the discovery of highly potent compounds with in-vivo chymotrypsin-like inhibitory activity. Here we present the detailed SAR, in-vitro and in-vivo proteasome activity of PI-184 class of compounds as potential anti-cancer agents. 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 3894. doi:1538-7445.AM2012-3894
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-3894
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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