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  • Ki, Min-Hyo  (8)
  • Park, Yongbin  (8)
  • 1
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    Abstract 1454: Antitumor activity of a selective FAK/Pyk2 inhibitor, SJP1602 against TNBC as well as CRC
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1454-1454
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1454-1454
    Abstract: Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that serves as a key mediator in response to integrin and growth factor signaling to control multiple aspects of cellular behavior. High expression and/or aberrant activation of FAK is observed in a broad range of human cancers, contributing to malignant phenotype in cancer and development of tumor resistance. FAK, therefore, has been a prominent target in oncology and a small number of FAK inhibitors are currently in clinical development. However, selective FAK inhibitors have shown insufficient antitumor responses due to a potential compensatory role of proline-rich tyrosine kinase 2 (Pyk2), a homologue of FAK, and require dual specific FAK/Pyk2 inhibition. SJP1602 is a novel dual inhibitor of FAK and Pyk2 without multi-kinase inhibition. We have previously reported that SJP1602 is highly specific against FAK and Pyk2 and its antitumor efficacy in triple negative breast cancer (TNBC) is superior over the clinically active FAK inhibitors. In this study, we further assessed pharmacological efficacy of SJP1602 in another type of cancer, colorectal cancer (CRC). As evaluated by cell-based ELISA, SJP1602 has nanomolar potency against FAK and Pyk2 in a panel of CRC cell lines. Validation through immunoblotting analyses revealed significant reduction of FAK/Pyk2 activation by treatment of SJP1602 in CRC cell lines, consistent with previous observations in TNBC cell lines. We then investigated the inhibition efficiency of SJP1602 in three-dimensional (3D) spheroid models using the CRC cell lines. As determined by CellTiter-Glo 3D cell viability assay, SJP1602 showed the significantly lower IC50 values than other FAK inhibitors. Next, to investigate the mechanism of action (MOA) of SJP1602, we examined changes in activation of several FAK/Pyk2-mediated signaling pathways. As shown by immunoblotting analyses, SJP1602 decreased JAK2 and Akt activity and increased the expression levels of cleaved caspase 3, a critical marker of apoptosis. Further assessment of SJP1602 in vivo showed significant antitumor activities in different human CRC xenograft models containing BRAF-mutant or KRAS-mutant tumors. In addition, the specificity and MOA of SJP1602 were confirmed using xenograft tumors. In consistent with in vitro results, SJP1602 reduced JAK2 and Akt activity in tumors from mice with SJP1602 administration. Therefore, our results demonstrate that SJP1602 has the strong antitumor efficacy in vitro and in vivo via downregulation of JAK2 and PI3K/Akt signaling pathways. SJP1602 is currently undergoing preclinical toxicology studies and in vitro safety evaluation. Taken together, our data provides promising preclinical results for the further development of SJP1602 as a potent anti-cancer agent in TNBC, CRC and resistant cancer involving FAK activation. Citation Format: Kug Hwa Lee, Hyoung Min Cho, Yongbin Park, Sungpyo Hong, Soon Kil Ahn, Min-Hyo Ki. Antitumor activity of a selective FAK/Pyk2 inhibitor, SJP1602 against TNBC as well as CRC [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 1454.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-1454
    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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    Abstract 4212: SJP1602, a selective and dual inhibitor of FAK and Pyk2 for treatment of triple negative breast cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 4212-4212
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 4212-4212
    Abstract: Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer, classified by a lack of ER and PR, and HER2 overexpression. Attributable to its tumor heterogeneity and a high rate of relapse, TNBC carries poor prognosis accounting for 30% mortality of breast cancer patients. Nevertheless, the current therapeutic options for patients with TNBC are limited to chemotherapy, lacking effective targeted therapies. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase mainly known for its role in tumor progression to a malignant phenotype and its involvement in resistance to conventional therapy. Its over-expression and/or activation is associated with poor survival in various types of cancer including TNBC. With increasing evidence of FAK as a promising therapeutic target in cancer, several small molecule inhibitors targeting FAK are currently on development and among them are defactinib (VS-6063) and GSK2256098, which are currently undergoing clinical investigation in combinatorial approach in solid tumors. In this study, we represent a novel small molecule inhibitor, SJP1602, targeting FAK and its homolog Proline-rich tyrosine kinase 2 (Pyk2). Biochemical kinase profiling of SJP1602 showed its greater selectivity for FAK and Pyk2, compared with VS-6063. Moreover, in vitro evaluation of SJP1602 using 3D spheroid models demonstrated that GI50 values of SJP1602 for spheroid growth of various TNBC cell lines were significantly lower than GI50 values of VS-6063 and GSK2256098. SJP1602 also attenuated spheroid formation along with decreased CD44 expression in MDA-MB-231 cells, implicating its capability to suppress the activity of cancer stem cells. In addition, SJP1602 remarkably reduced the invasive potential of MDA-MB-231 cells in 3D conditions, decreasing levels of the EMT-related protein, snail. More importantly, we confirmed the in vivo antitumor activity of SJP1602 compared with VS-6063 in MDA-MB-231 and BT-549 xenograft mouse models that display mesenchymal tumors with invasive and stem-like phenotype. As the result, SJP1602 exhibited substantial inhibitory effects on tumor growth in both xenograft models. In addition, assessment studies of ADME revealed the excellent plasma stability and liver microsomal metabolic stability of SJP1602 in human. Furthermore, therapeutic index estimated by comparison of AUC at toxic and effective doses was higher than 10, rendering its potential clinical safety and efficacy. Taken together, these findings suggest SJP1602 as a small molecule inhibitor targeting FAK and Pyk2 with its outstanding selectivity and anti-tumor efficacy. Therefore, SJP1602 could be a promising therapeutic agent for TNBC patients that are resistant to conventional therapy as well as for cancer patients with drug resistance involving FAK activation. Citation Format: Kug Hwa Lee, Hyoung Min Cho, Kwangwoo Hwang, Yongbin Park, Sungpyo Hong, Soon Kil Ahn, Min-Hyo Ki. SJP1602, a selective and dual inhibitor of FAK and Pyk2 for treatment of triple negative breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4212.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-4212
    RVK:
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    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 3
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    Abstract 5152: SJP1604, a nucleolin-targeted therapeutic agent for relapsed/refractory acute myeloid leukemia
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5152-5152
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5152-5152
    Abstract: Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are cancers characterized by the rapid growth of abnormal white blood cells. Although the standard first-line therapy leads to high rates of remission, approximately 30% of the treated patients are refractory and more than 50% of them face a relapse because of the occurrence of drug resistance and high toxicity. Therefore, there is a strong unmet medical need for the next-generation targeted therapy to overcome drug resistance and reduce toxicity in AML/MDS. Here, we designed an aptamer-drug conjugate (SJP1604) specific for nucleolin, which is highly expressed only on the cell membrane of cancer cells including AML cells. We identified that SJP1604 (APTA-16) inhibited the growth of AML cells and drug-resistant AML cells in vitro. SJP1604 presented outstanding anti-leukemic efficacy in vivo via syngeneic mouse model and xenograft mouse model. In addition, the synergistic effects were observed upon combination treatmeant with venetoclax in vitro. We also figured out that nucleolin as a clinical biomarker was significantly highly expressed on relapsed/refractory (R/R) AML patient-derived bone marrow cells ex vivo. SJP1604 selectively targeted cancer cells by nucleolin-binding on cell membrane with its high targeting ability and plasma stability owing to its unique conformational property, therefore, it demonstrated less cytotoxicity in vitro/in vivo and a superior therapeutic index based on AUC comparison in pharmacokinetic studies. The mechanism of the anti-leukemic efficacy of SJP1604 was also studied. First of all, SJP1604 decreased the expression of nucleolin and inactivated NFκB signaling pathway via dephosphorylation of NFκB, which resulted in diminished expression of DNMT1 followed by restored p15 expression. In addition, SJP1604 increased p53 expression and decreased bcl-2 expression in the protein and mRNA level. These could be one of potential mechanism of anti-leukemogenesis of SJP1604. In conclusion, these findings suggest that SJP1604 targeting nucleolin could be developed as a first-in-class drug for relapsed/refractory AML and MDS. GLP safety/toxicology studies of SJP1604 have been completed and clinical trials will be initiated in 2020. Citation Format: Jihyun Um, Dohyeong Lee, Yongbin Park, Sung Hwan Moon, Soo Jin Lee, Min-Hyo Ki. SJP1604, a nucleolin-targeted therapeutic agent for relapsed/refractory acute myeloid leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5152.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-5152
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 4
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    Abstract 1946: SJP1604, a novel nucleolin-targeted anti-cancer drug for acute myeloid leukemia using aptamer-drug conjugation technology
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1946-1946
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1946-1946
    Abstract: Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are cancers characterized by the rapid growth of abnormal white blood cells. Generally, cytarabine (Ara-C), azacitidine, and decitabine are treated as the standard first-line chemotherapy for AML/MDS. Although the therapy leads to high rates of remission, approximately 30% of the treated patients are refractory and more than 50% of them face a relapse because of the occurrence of drug resistance and high toxicity. Therefore, there is a strong unmet need for the next-generation targeted therapy to overcome drug resistance and reduce toxicity in AML/MDS. Aptamers mostly consist of oligonucleotides, which can specifically bind to their target molecules with high affinity. Here, we designed a synthetic DNA aptamer-nucleoside drug conjugate (SJP1604) specific for nucleolin, which is highly expressed only on the cell membrane of cancer cells. In particular, AML and ALL (acute lymphoblastic leukemia) cells are known to express the highest mRNA level of nucleolin among various cancer cells, relatively. Owing to the unique conformational property of SJP1604, it can be delivered into cancer cells with its high targeting ability and plasma stability. In this study, we verified that SJP1604 selectively targeted cancer cells by nucleolin-binding on the cancer cell membrane in the drug uptake assay. SJP1604 also exhibited a long-lasting plasma stability in 50% human plasma up to 48 hours in sharp contrast to unstability of general aptamers. Furthermore, SJP1604 inhibited not only the growth of human AML/MDS cell lines (MV-4-11, HL-60, MOLM-13, THP-1 and KG-1) but also drug-resistant cell lines (cytarabine-, azacitidine- and decitabine-resistant MOLM-13, cytarabine-resistant HL60 and cytarabine-resistant MV-4-11). Interestingly, SJP1604 showed the significantly reduced IC50 values with the decreased expression level of nucleolin in cytarabine-, azacitidine- and decitabine-resistant MOLM-13 while cytarabine caused no effect on the cell growth and the expression of nucleolin of the same resistant cell lines. Intravenous administration of SJP1604 (150 mg/kg) led to tumor regression and improved survival rate in MOLM-13 xenograft mouse model. In conclusion, these findings suggest that SJP1604 could be developed as a first-in-class drug for novel targeted therapy of AML/MDS with less drug toxicity as well as an orphan drug for overcoming drug resistance of AML/MDS, using aptamer-drug conjugation technology. Citation Format: Jihyun Um, Dohyeong Lee, Yongbin Park, Sung Hwan Moon, Su Jin Lee, Min-Hyo Ki, Hee Jong Shin, Eui Hwan Jo. SJP1604, a novel nucleolin-targeted anti-cancer drug for acute myeloid leukemia using aptamer-drug conjugation technology [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 1946.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-1946
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 5
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    Abstract 1430: In vivo PoC study and design for Phase I clinical study of SJP1604, a nucleolin-targeted therapeutic agent to treat entire population of relapsed/refractory acute myeloid leukemia patients
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1430-1430
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1430-1430
    Abstract: SJP1604 (APTA-16) is an aptamer-drug conjugate (APTA-DC) specifically targeting nucleolin, which is highly expressed only on the cell membrane of acute myeloid leukemia (AML) cells including relapsed/refractory aute myeloid leukemia (R/R AML). We previously presented the outstanding anti-leukemic activity of SJP1604 on AML cells including drug-resistant AML cells while standard chemotherapies showed no efficacy in vitro and in vivo. Therefore, we were able to conclude that only SJP1604 exhibits excellent resistance overcoming efficacy regardless of genetic defects of AML cells. Additionally, we recently identified that SJP1604 markedly eradicated AML cell engraftment with decreasing expression level of nucleolin protein in the bone marrow cells of MOLM-13 xenograft mouse model. These findings demonstrate that SJP1604 contributes to anti-leukemic effects through the regulation of nucleolin protein. We also figured out that nucleolin as a clinical biomarker was significantly highly expressed on AML and R/R AML patient-derived bone marrow cells. In particular, nucleolin expression is highly overexpressed in the bone marrow cells of entire population of R/R AML patients. Upto recent, considered as one of the major targeted therapeutics for AML, FLT3 inhibitors can target 25-30% of AML patients only. Therefore, our results mentioned above are very noteworthy finding showing the high potential of SJP1604 to be further developed as the first innovative targeted therapy to treat entire population of R/R AML patients. Herein, we show a phase I clinical trial design of SJP1604 to perform an open-label, first-in-human, dose escalation study to evaluate the safety, tolerability, pharmacokinetics and anti-tumor activity in patients with R/R AML. Citation Format: Jihyun Um, Dohyeong Lee, So Hee Kim, Eun-Hye Huh, Yongbin Park, Sung Hwan Moon, Soo Jin Lee, Je-Hwan Lee, Min-Hyo Ki. In vivo PoC study and design for Phase I clinical study of SJP1604, a nucleolin-targeted therapeutic agent to treat entire population of relapsed/refractory acute myeloid leukemia patients [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 1430.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-1430
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 6
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    Abstract 344: SJP1604, a novel targeted therapeutic agent for AML (acute myeloid leukemia) including standard therapy-resistant AML
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 344-344
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 344-344
    Abstract: Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are cancers characterized by the rapid growth of abnormal white blood cells. Generally, cytarabine (Ara-C), azacitidine, and decitabine are treated as the standard first-line chemotherapy for AML/MDS. Although the therapy leads to high rates of remission, approximately 30% of the treated patients are refractory and more than 50% of them face a relapse because of the occurrence of drug resistance and high toxicity. Therefore, there is a strong unmet need for the next-generation targeted therapy to overcome drug resistance and reduce toxicity in AML/MDS. Here, we designed an aptamer-nucleoside drug conjugate (SJP1604) via utilizing easy and continuous synthesis specific for nucleolin, which is highly expressed only on the cell membrane of cancer cells. In particular, AML, CLL (chronic lymphoblastic leukemia) and ALL (acute lymphoblastic leukemia) cells are known to express the highest mRNA level of nucleolin among various cancer cells, relatively. SJP1604 can be delivered into cancer cells with its high targeting ability and plasma stability via its unique conformational property. In this study, we verified that SJP1604 selectively targeted cancer cells by nucleolin-binding on the cancer cell membrane in the drug uptake assay. Owing to the selectivity, SJP1604 demonstrated less cytotoxicity on murine bone marrow cells in vitro and mouse white blood cells in vivo. SJP1604 also exhibited a long-lasting plasma stability in 50% human plasma up to 48 hours in contrast to unstability of general aptamers. Furthermore, SJP1604 inhibited the growth of various human AML/MDS cancer cells. Interestingly, SJP1604 showed the significantly reduced IC50 values with the decreased expression level of nucleolin in cytarabine-, azacitidine- and decitabine-resistant MOLM-13 while cytarabine caused no effect on the cell growth and the expression of nucleolin of the same resistant cell lines. Injection of SJP1604 led to tumor regression and improved survival rate in MOLM-13 xenograft mouse model and C1498 syngeneic mouse model. In ex vivo study, we figured out that the expression level of nucleolin is highly up-regulated in AML patient-derived bone marrow cells and the level is much higher in relapsed/refractory (R/R) AML patient-derived bone marrow cells. Moreover, SJP1604 also significantly reduced the colony forming unit (CFU) of R/R AML patient-derived bone marrow cells compared to that of AS1411 treatment. In conclusion, these findings suggest that SJP1604 could be developed as a first-in-class drug for novel targeted therapy of AML/MDS with less drug toxicity as well as as a remarkable orphan drug for overcoming drug resistance of AML/MDS in which distinctive solutions do not exist up until recently. Citation Format: Jihyun Um, Dohyeong Lee, Jisun Oh, Yongbin Park, Sung Hwan Moon, Su Jin Lee, Min-Hyo Ki, Eui Hwan Cho. SJP1604, a novel targeted therapeutic agent for AML (acute myeloid leukemia) including standard therapy-resistant AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 344.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-344
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    detail.hit.zdb_id: 410466-3
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  • 7
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    Abstract 1742: Dual inhibitor of immunokinase and pan-RAF for the treatment of KRAS-mutated cancers
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1742-1742
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1742-1742
    Abstract: Tumor-associated macrophages (TAMs) represent most of the white blood cell population in solid tumors. TAMs usually display an M2-like phenotype due to signals from the tumor microenvironment, such as IL-10, VEGFA and CSF-1/M-CSF. These anti-inflammatory and pro-tumorigenic macrophages promote tumor growth and metastasis. The presence of TAMs is usually correlated with a poor clinical outcome in cancer patients. Modulation of the immunosuppressive factors within the tumor microenvironment is a key issue in tumor immunology. TAMs subvert the anti-cancer function of tumor-infiltrating T lymphocytes. TAMs also modify the immune cell population within the tumor microenvironment to decrease anti-tumor immune cells while simultaneously increase the immunosuppressive cell population to promote tumorigenesis. As a result, targeting of TAMs may be a promising new approach to cancer treatment. CSF-1 is the crucial growth and differentiation factor for macrophage and CSF-1R is exclusively expressed by cells of the monocyte lineage, suggesting that CSF-1R is an attractive therapeutic target to enable interference with TAMs. In preclinical models, macrophage depletion by CSF-1R inhibitor increased the antitumor effects of VEGF-targeted therapies. Furthermore, failure of antiangiogenic therapy is caused by the pro-angiogenic Tie2-expressing monocytes infiltrating tumor tissues. These data provide the rationale for the combination of antiangiogenic drugs with macrophage targeting strategies to increase the therapeutic efficacy and to prevent drug resistance. Therefore, we tried to find inhibitors of immunokinase using structure-based molecular modeling and identified a selective inhibitor, SJP-1601. SJP-1601 potentially inhibited CSF-1R, Tie2, and VEGFR2 in vitro kinase assay. Interestingly, SJP-1601 also inhibited B-RAF, C-RAF and B-RAF V600E in kinase panel assay. We orally administered SJP-1601 in colorectal cancer xenografts with mutant K-RAS and observed the dose-dependent reduction of tumor volume. In addition, oral administration of SJP-1601 attenuated tumor growth correlated with enriched CD8+ T cells and decreased regulatory T cells in tumor stroma in BALB/c mice bearing 4T1 tumor cells or C57BL/6 mice bearing MC38 tumor cells. These data confirmed the preclinical merit of CSF1-CSF1R signaling blockade alone or as a part of combinatorial therapies to offer synergistic immunotherapeutic effects in treatments of human cancer. In this study, we discovered an orally active dual inhibitor of immunokinase & pan-RAF. SJP-1601 not only improved the efficacy of adoptive T cell therapy through inhibition of immunosuppressive macrophage recruitment and activation in immunocompetent mice but also potentiated the response of xenograft with mutant KRAS by preventing pan-RAF. Our findings suggest that SJP-1601 could be an excellent preclinical candidate for the treatment of cancer with mutant K-RAS. Citation Format: Sungpyo Hong, Soon Kil Ahn, Ho-Seok Kwon, Yongbin Park, Min-Hyo Ki, Hee Jong Shin. Dual inhibitor of immunokinase and pan-RAF for the treatment of KRAS-mutated cancers [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 1742.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-1742
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 8
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    Abstract 1295: SJP1901, a small molecule inhibitor targeting hippo pathway by directly inhibiting TEAD palmitoylation in hippo pathway-dependent cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1295-1295
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1295-1295
    Abstract: The hippo pathway is a critical transcriptional regulator of cell growth, proliferation, and migration in cancer, furthermore,YAP-TEAD complexes act as a major role in the pathway. S-palmitoylation of cysteine residues in TEAD proteins is required for their stability and function in hippo pathway signaling. Recently, it has become manifested that the dysregulation of hippo pathway effectors (MST1/2 and LATS1/2) is involved in oncogenesis. These effectors inactivate translocation of YAP and TAZ into the nucleus. The translocation of YAP/TAZ is responsible for acting as transcriptional coactivators by binding to the transcription factor, TEADs resulting in the transcription of cancer-related genes that drive tumor growth. Since YAP/TAZ are considered to be natively unfolded and can be difficult to handle as a drug target, TEAD is regarded as an excellent therapeutic target for intervention of the hippo pathway. SJP1901 is a small molecule of TEAD inhibitor with potential as drug candidates in malignant mesothelioma and other types of cancer. Based on the results of structure-based drug design, hit compounds were synthesized and their efficacy was evaluated.The compounds effectively inhibited palmitoylation of TEAD proteins and showed remarkable efficacy in reporter gene assay using TEAD responsive element (TRE)-integrated MCF7 with nano molar IC50 concentrations. The excellent anti-tumor effect of SJP1901 was revealed via cell proliferation inhibition assay (nano molar IC50 concentrations) andanalysis of inhibited transcription activity for target genes (CTGF and CYR61) usingmalignant mesothelia cell lines (NCI-H226, NCI-H2052 and MSTO-211H) known to display hippo pathway-dependent cell growth. In addition, these compounds showed lower toxicities in normal cells such as Fa2N4, CCD-18co and WI38 (IC50 & gt;10 μM). In conclusion, we obtained potent small molecules which inactivate TEAD proteins by directly inhibiting their palmitoylation. SJP1901 showed outstanding anti-cancer effects through regulating hippo pathway-mediated target genes and lower toxicitiy in normal cells. In vivo efficacy study and research to expand the indications are currently ongoing. Citation Format: Jihyun Um, Janghyun Lee, Kwangwoo Hwang, Sujin Park, Jooyoung Hyun, Dohyeong Lee, Jeongmin Lee, Li-Kyung Kim, Moon Jung Back, Seong Jun Park, Hwan Jung Lim, You-Keun Shin, Hei-Cheul Jeung, Jaewoong Lee, Hyun Tae Kim, Yongbin Park, Hoseok Kwon, Min-Hyo Ki. SJP1901, a small molecule inhibitor targeting hippo pathway by directly inhibiting TEAD palmitoylation in hippo pathway-dependent cancer [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 1295.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-1295
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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