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  • 1
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    Online Resource
    Abstract 739: Preclinical and clinical activity of SAR439859, Amcenestrant, a next generation SERD
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 739-739
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 739-739
    Abstract: Primary treatment for estrogen receptor-positive (ER+) breast cancer is endocrine therapy. Selective estrogen receptor degraders (SERDs), such as fulvestrant, induce effective ER signaling inhibition, although clinical studies with fulvestrant report insufficient blockade of ER signaling, possibly due to suboptimal pharmaceutical properties. Here we describe the discovery of SAR439859 (Amcenestrant), a novel, orally bioavailable SERD with potent antagonist and degradation activities against both wild-type and mutant Y537S ER. Driven by its fluoropropyl pyrrolidinyl side chain, SAR439859 has demonstrated broader and superior ER antagonist and degrader activities across a large panel of ER+ cells, compared with other SERDs including improved inhibition of ER signaling and tumor cell growth. Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ breast cancer models including MCF7-ESR1 mutant-Y537S mouse tumors and HCI013, a patient-derived tamoxifen-resistant xenograft tumor. Importantly, in these mutant ESR1 models, we demonstrate that the efficacy of SAR439859 was increased when coadministered with palbociclib, an inhibitor of cyclin-dependent kinase 4 and 6. In the clinical setting, SAR439859 also demonstrated a high level of target engagement, ER degradation and inhibition of ER signaling as well as encouraging anti-tumor activity in heavily pretreated patients with advanced or metastatic ER-positive breast cancer. These findings indicate that SAR439859 would provide therapeutic benefit to patients with ER+ breast cancer, including those who are resistant to endocrine therapy with both wild-type and mutant ER. Citation Format: Maysoun Shomali, Fangxian Sun, Laurent Besret, Anne Caron, Joon Sang Lee, Youssef El-Ahmed, Laurent Schio, Jack Pollard, Vasiliki Pelekanou, Patrick Cohen, Marina Celanovic, Christina Herold, Chris Soria, Laurent Debussche, Monsif Bouaboula. Preclinical and clinical activity of SAR439859, Amcenestrant, a next generation SERD [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 739.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-739
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
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    Abstract 5775: Identification of SAR439859, an orally bioavailable selective estrogen receptor degrader (SERD) that has strong anti-tumor activity in wild-type and mutant ER+ breast cancer models
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 5775-5775
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 5775-5775
    Abstract: Nearly 70% or more of newly diagnosed cases of breast cancer (BC) are estrogen receptor positive (ER+) where endocrine therapy is a primary treatment. However, substantial evidence describes a continued role of ER signaling in tumor progression, where approximately 40% of patients on endocrine therapy develop resistance that include mutations in the ER that drive a constitutively active receptor. Fulvestrant, an estrogen receptor degrader, is effective at shutting down ER signaling. However, fulvestrant efficacy studies report insufficient blockade of ER signaling in patients that may be a consequence of poor pharmaceutical properties. Here we describe the discovery of SAR439859, a novel, orally bioavailable SERD with potent antagonist and degradative properties against ER both in vitro and in vivo. SAR439859 has robust inhibition of ER signaling activity in multiple ER+ breast cancer cell lines including tamoxifen resistant lines harboring ER mutations. Across a large panel of ER+ cells, SAR439859 demonstrated broad and superior ER degradation activity as compared to other SERDs including improved inhibition of ER signaling and inhibition of cell growth. Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ BC models including MCF7-ESR1 mutant-Y537S model and endocrine therapy resistant patient-derived xenograft tumor transplantation. Collectively, these results showed that SAR439859 is an oral, nonsteroidal, selective estrogen receptor antagonist and degrader that could provide therapeutic benefit to ER+ breast cancer patients. SAR439859 is currently being evaluated in a phase I clinical trial. Citation Format: Maysoun Shomali, Youssef El-Ahmad, Frank Halley, Jane Cheng, Michael Weinstein, Muchun Wang, Fangxian Sun, Natalia Malkova, Mikhail Levit, Malvika Koundinya, Zhuyan Gou, Andrew Hebert, Jessica McManus, Dietmar Hoffman, Hui Cao, Joonil Jung, Jack Pollard, Sylvie Vincent, Timothy Ackerson, Francisco Adrian, Chris Winter, Victoria Richon, Hong Chen, Karl Hsu, Joanne Lager, Albane Courjaud, Rosalia Arrebola, Laurent Besret, Pierre-Yves Abecassis, Laurent Schio, Gary McCort, Michel Tabart, Victor Certal, Fabienne Thompson, Bruno Filoche-Rommé, Laurent Debussche, Patrick Cohen, Carlos Garcia-Echeverria, Monsif Bouaboula. Identification of SAR439859, an orally bioavailable selective estrogen receptor degrader (SERD) that has strong anti-tumor activity in wild-type and mutant ER+ breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5775.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-5775
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
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    Abstract 943: SAR439859, an orally bioavailable selective estrogen receptor degrader (SERD) that demonstrates robust antitumor efficacy and limited cross-resistance in ER+ breast cancer
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 943-943
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 943-943
    Abstract: Despite resistance to endocrine therapies, estrogen receptor-positive (ER+) breast cancers (BC) still rely on ER. Eliminating ER by inducing its degradation with selective ER downregulators (SERD) should induce complete ablation of ER pathways. The clinical SERD fulvestrant, although it has demonstrated clinical benefits, is hampered by its poor drug properties and undesirable pharmacokinetics, undermining its optimal clinical activity. Therefore there is an unmet need for an improved therapy targeting ER. Here we describe SAR439859, a novel, nonsteroidal, orally bioavailable SERD currently in clinical trials. SAR439859 has a potent ER antagonist and ER degrading activity that translates in a robust inhibition of ER signaling in multiple ER+ breast cancer cell lines, including tamoxifen-resistant lines as well as cell lines harboring ER mutations. SAR439859 displays a broad and superior ER degradation activity across a large panel of ER+ cells. Importantly, based on its mechanism of action SAR439859 shows limited cross-resistance with other clinical SERD molecules. SAR439859 induces strong in vivo antitumor activity against a variety of BC cell lines and patient-derived xenografts, including models that harbor ERα mutations. The transcriptional profile analysis highlighted a crosstalk of ER mutant signaling and other oncogenic pathways. Interestingly, CDK4/6 inhibition by palbociclib induces partial activation of ER pathways as potential mechanism of tumor escape, which is completely abolished by the combination of SAR439859 with palbociclib. Finally, we demonstrate that SAR439859 in combination with palbociclib can lead to higher in vivo efficacy. This study highlights novel mechanism of ER degradation by SAR439859 that leads to profound inhibition of ER signaling as well as modulation of other oncogenic pathways and provides rationale for the ongoing clinical investigation of SAR439859 in ER+ breast cancer patients, both as a single agent and in combination with approved agents, such as CDK4 inhibitor. Citation Format: Monsif Bouaboula, Maysoun Shomali, Jane Cheng, Natalia Malkova, Fangxian Sun, Malvika Koundinya, Zhuyan Guo, Stephane Poirier, Mikhail Levit, Dietmar Hoffman, Hui Cao, Laurent Bestret, Francisco Adrian, Christoph Winter, Youssef El-Ahmad, Sylvie Vincent, Frank Halley, Gary McCort, Laurent Schio, Vicky Richon, Hong Cheng, Karl Hsu, Chris Soria, Patrick Cohen, Joanne Lager, Carlos Garcia-Echeverria, Laurent Debussche. SAR439859, an orally bioavailable selective estrogen receptor degrader (SERD) that demonstrates robust antitumor efficacy and limited cross-resistance in ER+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 943.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-943
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
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    SAR439859, a Novel Selective Estrogen Receptor Degrader (SERD), Demonstrates Effective and Broad Antitumor Activity in Wild-Type and Mutant ER-Positive Breast Cancer Models
    American Association for Cancer Research (AACR) ; 2021
    In:  Molecular Cancer Therapeutics Vol. 20, No. 2 ( 2021-02-01), p. 250-262
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 20, No. 2 ( 2021-02-01), p. 250-262
    Abstract: Primary treatment for estrogen receptor-positive (ER+) breast cancer is endocrine therapy. However, substantial evidence indicates a continued role for ER signaling in tumor progression. Selective estrogen receptor degraders (SERD), such as fulvestrant, induce effective ER signaling inhibition, although clinical studies with fulvestrant report insufficient blockade of ER signaling, possibly due to suboptimal pharmaceutical properties. Furthermore, activating mutations in the ER have emerged as a resistance mechanism to current endocrine therapies. New oral SERDs with improved drug properties are under clinical investigation, but the biological profile that could translate to improved therapeutic benefit remains unclear. Here, we describe the discovery of SAR439859, a novel, orally bioavailable SERD with potent antagonist and degradation activities against both wild-type and mutant Y537S ER. Driven by its fluoropropyl pyrrolidinyl side chain, SAR439859 has demonstrated broader and superior ER antagonist and degrader activities across a large panel of ER+ cells, compared with other SERDs characterized by a cinnamic acid side chain, including improved inhibition of ER signaling and tumor cell growth. Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ breast cancer models, including MCF7-ESR1 wild-type and mutant-Y537S mouse tumors, and HCI013, a patient-derived tamoxifen-resistant xenograft tumor. These findings indicate that SAR439859 may provide therapeutic benefit to patients with ER+ breast cancer, including those who have resistance to endocrine therapy with both wild-type and mutant ER.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-20-0390
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 5
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    MBP1: a novel mutant p53-specific protein partner with oncogenic properties
    Springer Science and Business Media LLC ; 1999
    In:  Oncogene Vol. 18, No. 24 ( 1999-06-17), p. 3608-3616
    Details
    In: Oncogene, Springer Science and Business Media LLC, Vol. 18, No. 24 ( 1999-06-17), p. 3608-3616
    Type of Medium: Online Resource
    ISSN: 0950-9232 , 1476-5594
    URL: Article
    DOI: 10.1038/sj.onc.1202937
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 1999
    detail.hit.zdb_id: 2008404-3
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  • 6
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    A tumor specific single chain antibody dependent gene expression system
    Springer Science and Business Media LLC ; 1999
    In:  Oncogene Vol. 18, No. 2 ( 1999-01-14), p. 559-564
    Details
    In: Oncogene, Springer Science and Business Media LLC, Vol. 18, No. 2 ( 1999-01-14), p. 559-564
    Type of Medium: Online Resource
    ISSN: 0950-9232 , 1476-5594
    URL: Article
    DOI: 10.1038/sj.onc.1202377
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 1999
    detail.hit.zdb_id: 2008404-3
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  • 7
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    Abstract 805: Disruption of the MDM2-p53 interaction synergizes with MEK inhibition to induce cell death and promote tumor regression in p53 wild-type, Ras or Raf-mutant tumor models
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 805-805
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 805-805
    Abstract: Disruption of the interaction between p53 and MDM2 with small molecules, and subsequent reactivation of p53, is an attractive treatment strategy for p53 wild-type tumors that has shown striking pre-clinical activity in models exhibiting genomic amplification of the MDM2 gene. However, MDM2 amplified tumors represent only a small proportion of the p53 wild-type tumor population, and single agent regressions may be limited outside of the MDM2 amplified context. In order to increase the potential clinical benefit of MDM2-p53 protein-protein interaction (PPI) inhibitors beyond tumors exhibiting amplification of MDM2, we performed an enhancer library combination screen to identify optimal combination partners for MDM2-p53 PPI inhibitors in p53 wild-type, MDM2 non-amplified tumor cells. The MDM2-p53 PPI inhibitor SAR405838 and a related molecule were examined in combination with an enhancer library of 200 oncology drugs representing a broad molecular diversity of targets across a panel of twenty p53 wild-type cancer cell lines. Analysis results showed that MEK inhibitors were the most statistically significant synergistic combination partners in this screen, with synergy observed in cell lines harboring mutations that activated MAP kinase pathway signaling. These synergy results were validated in independent experiments using the ray design methodology, and extended to multiple K-ras, N-ras and B-raf mutant contexts in vitro. In K-ras, N-ras or B-raf mutant cell lines, the combination of SAR405838 with the MEK inhibitor pimasertib resulted in p53 pathway activation, inhibition of pERK levels, induction of the apoptotic mediators PUMA and BIM, induction of phosphatidyl serine exposure, and induction of caspase activity. In the Ras/Raf wild-type cell line MCF7, no synergy was observed. In cell line and patient-derived xenografts in vivo, the combination of SAR405838 and pimasertib resulted in greater anti-tumor activity than single agents and induced regression in K-ras, N-ras and B-raf mutant tumor models derived from different tissue types, including complete regressions in multiple models. These data indicate that MEK inhibitors synergize with MDM2-p53 PPI inhibitors in tumor models that exhibit activated MAP kinase pathway signaling and p53 wild-type status. Given the relative lack of overlapping clinically significant toxicities of MDM2-p53 PPI inhibitors and MEK inhibitors, such a combination merits further investigation for the treatment of K-ras, N-ras, or B-raf mutant, p53 wild-type tumors, representing a large patient population with significant unmet medical need. Citation Format: Isabelle Meaux, Jean-Paul Nicolas, Steve Rowley, Sukhvinder Sidhu, Francoise Herve, Laurent Dassencourt, Fanny Windenberger, Dimitri Gorge-Bernat, Pascal Pannier, Donald Bergstrom, Laurent Debussche, James Watters. Disruption of the MDM2-p53 interaction synergizes with MEK inhibition to induce cell death and promote tumor regression in p53 wild-type, Ras or Raf-mutant tumor models. [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 805. doi:10.1158/1538-7445.AM2014-805
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-805
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
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    Abstract 4731: Cytotoxic versus cytostatic effects in tumor models by spiro-oxindole-based modulators of the MDM2-p53 interaction
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 4731-4731
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 4731-4731
    Abstract: Two spiro-oxindole-based modulators -compounds A and B - of the MDM2-p53 protein-protein interaction display suitable pharmacological properties and are currently under advanced preclinical development (1). In vitro, these compounds induce massive cell death in a subset of relevant tumor models such as MDM2-amplified SJSA-1, while they can significantly block cell proliferation without detectable cytotoxic effect in other human cell lines (e.g. HCT116). To better characterize in vivo the different tumor cell sensitivity of these novel MDM2 antagonists, quantitative and longitudinal pharmacodynamic effects have been determined in several preclinical settings: i) anti-tumor efficacy, ii) activation of p53-dependent molecular biomarkers such as p53 itself, p21, MDM2, PUMA, Noxa, Bax and MIC-1 and iii) downstream biological effects monitored by immuno-assays as well as by in vivo fluorescence tomography and PET imaging. The results obtained from these studies have revealed striking differences in the biological read-outs associated with the observed cytotoxic versus cytostatic effects and provide guidance for the use of certain biomarkers in the clinical development of this new generation of anti-cancer agents. 1. Wang S. et al., AACR, Orlando FL, 2011, Abstract LB-204 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 4731. doi:1538-7445.AM2012-4731
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-4731
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 9
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    SAR405838: An Optimized Inhibitor of MDM2–p53 Interaction That Induces Complete and Durable Tumor Regression
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 20 ( 2014-10-15), p. 5855-5865
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 20 ( 2014-10-15), p. 5855-5865
    Abstract: Blocking the oncoprotein murine double minute 2 (MDM2)–p53 protein–protein interaction has long been considered to offer a broad cancer therapeutic strategy, despite the potential risks of selecting tumors harboring p53 mutations that escape MDM2 control. In this study, we report a novel small-molecule inhibitor of the MDM2–p53 interaction, SAR405838 (MI-77301), that has been advanced into phase I clinical trials. SAR405838 binds to MDM2 with Ki = 0.88 nmol/L and has high specificity over other proteins. A cocrystal structure of the SAR405838:MDM2 complex shows that, in addition to mimicking three key p53 amino acid residues, the inhibitor captures additional interactions not observed in the p53–MDM2 complex and induces refolding of the short, unstructured MDM2 N-terminal region to achieve its high affinity. SAR405838 effectively activates wild-type p53 in vitro and in xenograft tumor tissue of leukemia and solid tumors, leading to p53-dependent cell-cycle arrest and/or apoptosis. At well-tolerated dose schedules, SAR405838 achieves either durable tumor regression or complete tumor growth inhibition in mouse xenograft models of SJSA-1 osteosarcoma, RS4;11 acute leukemia, LNCaP prostate cancer, and HCT-116 colon cancer. Remarkably, a single oral dose of SAR405838 is sufficient to achieve complete tumor regression in the SJSA-1 model. Mechanistically, robust transcriptional upregulation of PUMA induced by SAR405838 results in strong apoptosis in tumor tissue, leading to complete tumor regression. Our findings provide a preclinical basis upon which to evaluate SAR405838 as a therapeutic agent in patients whose tumors retain wild-type p53. Cancer Res; 74(20); 5855–65. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-14-0799
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 10
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    Abstract 4475: Discovery and characterization of PI3K isoform-selective inhibitors
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 4475-4475
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 4475-4475
    Abstract: Abnormal PI3K pathway activation plays a major role in cancer, as a result of either RTK activation or somatic mutations of major components of the pathway, including activating point mutations and amplification of the PIK3CA gene as well as loss of negative regulatory proteins such as PTEN. Most of the ATP-competitive PI3K inhibitors currently in clinical development inhibit all class I PI3K isoforms: however, several recent reports support the development of isoform-specific inhibitors. In particular, while PI3Kα specific inhibitors are predicted to inhibit growth of tumors with PIK3CA mutations, PTEN-deficient tumors have been shown to depend on PI3Kβ. In addition, isoform specific PI3K inhibitors may exhibit better safety profiles compared to pan-selective PI3K inhibitors, and thus may be easier to combine with other targeted or cytotoxic therapies. Here we report the discovery of ATP-competitive inhibitors with selectivity for PI3Kα, PI3Kα/mTOR, or PI3Kβ, which were identified and optimized by means of high-throughput screening and medicinal chemistry. These inhibitors exhibit biochemical IC50 values below 100 nM and good selectivity over other PI3K isoforms and a diverse panel of protein kinases. Cellular assays demonstrate that PI3Kα or PI3Kα/mTOR compounds inhibit phosphorylation of targets downstream of PI3K (Akt) and mTOR (S6 and p70S6 kinase) in the PI3Kα-activated MCF7 cell line, and that effects on PI3K pathway readouts are less pronounced in PC3 cells lacking PTEN. In contrast, PI3Kβ compounds potently inhibit phosphorylation of AKT (cellular IC50s & lt; 200 nM) in the PTEN-deficient PC3 tumor cell line, and the most PI3Kβ-selective inhibitors are inactive on AKT phosphorylation in PI3Kα-activated H460 cells. In vivo pharmacodynamic analyses following oral administration of these isoform-selective inhibitors to mice bearing xenografted tumors demonstrate dose-dependent inhibition of phosphorylation of PI3K and mTOR effectors at well-tolerated doses. These results strongly argue for the development of isoform-selective PI3K inhibitors for the treatment of cancer patients harboring tumors with PTEN- deficient or PI3Kα-activated specific genotypes. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4475.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-4475
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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