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  • 1
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    Online Resource
    Abstract LB139: VRN10, Discovery of Potent Irreversible HER2 Kinase Inhibitors with Intracranial Activity
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. LB139-LB139
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. LB139-LB139
    Abstract: Human epidermal growth factor receptor 2 (HER2) amplification is one of oncogenic drivers most found in breast cancer but also occurs in multiple other tumor types. Approximately 10-30% of patients with breast cancer develop brain metastases (BCBM), a devastating cause of morbidity and mortality. To address this unmet medical need, VRN10s, brain penetrant, orally bioavailable, and irreversible small molecule inhibitors were designed to target HER2 while sparing EGFR wild type. In biochemical assays VRN10s had low nanomolar potency to inhibit catalytic activity of HER2. In cell viability assays using HER2+ breast and gastric cancer cell lines, VRN10s inhibited proliferation with single-digit nanomolar potency and exhibited an exceptional selectivity for HER2 over EGFR, with an enhancement of & gt; 30-fold. Neuregulin-1 (NRG-1) has been suggested to decrease the anti-tumor activity of HER2 kinase inhibitors by induction of HER3 in brain microenvironment. Two FDA-approved HER2 kinase inhibitors tucatinib and lapatinib are not only less brain permeable, but they also show significantly decreased activity in the presence of NRG-1. However, the addition of NRG-1 did not rescue the proliferation of HER2+ breast cancer cell lines treated with VRN10s. Western blot confirmed that VRN10s inhibit signal transduction downstream of HER2 and HER3 through the AKT and ERK pathways. Inhibition of HER2 is reported to cause cytotoxicity on cardiomyocytes. In spite of potent inhibition of HER2 catalytic inhibition, VRN10s did not show cardiomyocyte cytotoxicity more than other HER2 kinase inhibitors, including tucatinib and neratinib. We confirm VRN10s to have high brain exposure in several preclinical models. Consistent with our in vitro results, potent activity was observed in the xenograft and intracranial models using once daily oral administration with strong tumor growth inhibition. Based on in vitro assay, brain permeability and in vivo efficacy, VRN10s may be promising therapeutic candidates for patients with HER2+ tumors including BCBM. Citation Format: Hwan Kim, Younho Lee, Jinhee Park, Youngyi Lee, Jieun Choi, Jihye Yoo, Chanmi Park, Somi Lee, Eunhwa Ko, Jung Beom Son, Hwan Geun Choi, Nam Doo Kim, Daekwon Kim, Sunghwan Kim. VRN10, Discovery of Potent Irreversible HER2 Kinase Inhibitors with Intracranial Activity [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 LB139.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-LB139
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 2
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    Online Resource
    Abstract P1-11-03: VRN101099, Brain Permeable HER2 Kinase Inhibitor, Shows the Anti-tumor Activity in Preclinical Models of HER2-positive Cancers
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 5_Supplement ( 2023-03-01), p. P1-11-03-P1-11-03
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. P1-11-03-P1-11-03
    Abstract: The brain is a common target organ for breast cancer metastasis, and the risk of brain metastasis is usually high for patients with HER2-positive breast cancer. While T-DXd showed positive results in HER2-positive breast cancer brain metastasis (BCBM), its activity and blood-brain barrier (BBB) permeability in active BCBM need to be further validated (TUXEDO-1 included 15 patients with active brain metastasis). Tucatinib plus Trastuzumab and Capecitabine triplet showed efficacy in patients with brain metastasis, but Tucatinib alone has poor BBB penetration. There is still an unmet medical need for active HER2-positive BCBM. VRN101099 is a highly selective kinase inhibitor of HER2 (Eurofins scanMAX Kinase Profiling, S-score (35) of 0.01). VRN101099 has single- to double-digit nanomolar (IC50) cellular potency in HER2-dependent cancer cells, and Ba/F3 cells expressing HER2 wild type or mutations with selectivity over wildtype EGFR. VRN101099 inhibited proliferation of BT474 with 3.6 nM IC50 but HaCaT with 829.2 nM IC50. VRN101099 binds HER2 kinase by forming a covalent bond to the Cys805 and its irreversible inhibition resulted in a longer target resident time than Tucatinib, confirmed by in vitro washout experiments. Robust in vivo activity of VRN101099 was observed in HER2-positive BT474 xenograft models. Moreover, once daily oral administration of VRN101099 significantly regressed intracranial BT474 tumor, demonstrating greater efficacy than twice daily oral administration of Tucatinib. These results were well explained by the superior brain to plasma exposure of VRN101099 to Tucatinib. Also, VRN101099 showed high exposure in the target organ, the fat pad, which potentiated better clinical translation. These anti-tumor efficacies are correlated with pharmacodynamic responses, as confirmed by decreased HER2, AKT, and ERK phosphorylation. In summary, VRN101099 is a brain penetrant, orally bioavailable, irreversible, and highly selective inhibitor of HER2 with therapeutic potential in HER2-positive BCBM. These data support the clinical development of VRN101099 in HER2-driven cancers. Citation Format: Yikyung Ko, Jihye yoo, Hong-ryul Jung, Hyerim Lim, YeongDeok Lee, Se Hyuk Kim, Dong Guk Shin, Serin Cho, Myung hoe Heo, Haelee Kim, Ha Yeon Cho, Ah Reum Han, Eunhwa Ko, Hwan Geun Choi, Deakwon Kim, Sunghwan Kim. VRN101099, Brain Permeable HER2 Kinase Inhibitor, Shows the Anti-tumor Activity in Preclinical Models of HER2-positive Cancers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-03.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS22-P1-11-03
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 3
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    FRTX-02, a selective and potent inhibitor of DYRK1A, modulates inflammatory pathways in mouse models of psoriasis and atopic dermatitis
    Elsevier BV ; 2023
    In:  Journal of Translational Autoimmunity Vol. 6 ( 2023), p. 100185-
    Details
    In: Journal of Translational Autoimmunity, Elsevier BV, Vol. 6 ( 2023), p. 100185-
    Type of Medium: Online Resource
    ISSN: 2589-9090
    URL: Article
    DOI: 10.1016/j.jtauto.2022.100185
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
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  • 4
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    Abstract P2-13-15: VRN101396, a brain-permeable HER2 inhibitor, shows the anti-tumor activity in preclinical HER2-positive cancer models
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 4_Supplement ( 2022-02-15), p. P2-13-15-P2-13-15
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. P2-13-15-P2-13-15
    Abstract: Breast cancer (BC) is the second most common cancer associated with brain metastasis (BM) and among patients with breast cancer brain metastasis (BCBM), human epidermal growth factor receptor 2 (HER2)-positive breast cancer is most likely to develop BM. The overall prognosis of HER2-positive BCBM remains dismal with median survival time after BM of less than a year. Drugs like T-DM1, T-DXd and Tucatinib are reported to deliver a progression-free survival benefit in HER2-positive BCBM patients, but there are still unmet needs for a drug that crosses the blood brain barrier more effectively. We develop VRN101396, a brain penetrant, orally available, and irreversible small molecule inhibitor targeting HER2 to offer a new therapeutic option for the treatment of HER2-positive BCBM. VRN101396 potently inhibits catalytic activity of HER2 but spares wild-type EGFR. In HER2-positive breast cancer cell lines BT474 and SK-BR3 and gastric cancer cell line NCI-N87, VRN101396 inhibited the cell proliferation and phosphorylation of HER2 with single- or double-digit nanomolar IC50 values while inhibiting wild type EGFR with an IC50 value of & gt;100 nM. In both subcutaneous and intracranial efficacy mouse models, once-daily oral dose of VRN101396 significantly inhibited tumor growth and achieved tumor regression. In N87 subcutaneous xenograft model, VRN101396 alone showed superior efficacy to the combination of Tucatinib and Trastuzumab. Additionally, in intracranial xenograft model, VRN101396 showed superior efficacy to Tucatinib. Pharmacokinetics of VRN101396 displayed higher brain exposure than tucatinib and lapatinib, indicating better target engagement in the brain. Pharmacodynamic analysis revealed that VRN101396 reduced phosphorylation of HER2, HER3, AKT, and ERK compared to vehicle group after administration up to 24 hours. In conclusion, VRN101396 is a therapeutic candidate for the treatment of HER2-positive BC, BCBM and gastric cancer. Citation Format: Hong-ryul Jung, Sunghwan Kim, Jihye Yoo, Chan mi Park, Somi Lee, Hyoju Lee, Youngyi Lee, Jinhee Park, Kyungah Seo, Dong-Hyuk Seo, Eunhwa Ko, Jung Beom Son, Deakwon Kim, Hwan Geun Choi, Nam Doo Kim. VRN101396, a brain-permeable HER2 inhibitor, shows the anti-tumor activity in preclinical HER2-positive cancer models [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-15.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS21-P2-13-15
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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