Discovery of an Indirubin Derivative as a Novel c-Met Kinase Inhibitor with <i>In Vitro</i> Anti-Tumor Effects

Ndolo, Karyn Muzinga; An, Su; Park, Kyeong Ryang; Lee, Hyo‐Jeong; Yoon, Kyoung Bin; Kim, Yong-Chul; Han, Sun‐Young

doi:10.4062/biomolther.2018.091

Cited by 11 publications

(6 citation statements)

References 23 publications

(29 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…c-Met-targeted therapy in GC mainly includes tyrosine kinase inhibitors, monoclonal antibodies, and c-Met-targeted adoptive immunotherapy. Tyrosine kinase inhibitors and monoclonal antibodies have shown obvious antitumor activity in cell and xenograft tumor models [ 21 – 25 ], while most tumors have not achieved prominent antitumor activity in clinical trials [ 6 , 26 ]. Only a few tumors have shown encouraging antitumor activity, especially in the treatment of NSCLC (non-small cell lung cancer) [ 27 , 28 ].…”

Section: Discussionmentioning

confidence: 99%

Study on the expression of c-Met in gastric cancer and its correlation with preoperative serum tumor markers and prognosis

et al. 2022

View full text Add to dashboard Cite

Background Studies have found that c-Met plays a critical role in the progression of solid tumors. This study aimed to investigate the expression of c-Met in gastric cancer (GC) and its correlation with preoperative serum tumor markers and prognosis, in order to provide a more theoretical basis for targeting c-Met in the treatment of GC. Methods Ninety-seven patients who underwent curative gastrectomy in our hospital from December 2013 to September 2015 were included in this study. The tissue microarray was constructed by paraffin-embedded tumor tissue of enrolled patients, including 97 GC points and 83 paracancerous points. Then, it was used for c-Met immunohistochemical staining, followed by an immunological H-score. The clinical baseline data and 5-year survival of patients with low and high c-Met expression were compared. Besides, the correlation between the expression of c-Met in tumor tissues and preoperative serum tumor markers was investigated. Finally, multivariate Cox regression analysis was used to explore the survival risk factors of patients. Results c-Met has a high expression rate in GC tissues 64.95% (63/97). The expression of c-Met was significantly different in different clinicopathological stages (p < 0.05); the high expression group also had a higher M stage and clinicopathological stage of GC. The correlation test between the c-Met H-score and CA125 was statistically significant (p = 0.004), indicating a positive correlation. Furthermore, high c-Met expression correlated with poor overall survival (OS) for 5 years (p = 0.005). It was also found that the high expression of c-Met in stage I–II patients was correlative with poor OS for 5 years (p = 0.026), while stage III–IV patients had no statistical significance (p > 0.05). Multivariate Cox regression analysis showed that c-Met might be an independent risk factor for survival 5 years after surgery. Conclusion This study found that the high expression of c-Met in GC tissues was associated with poor 5-year OS in GC patients and was an independent risk factor for 5-year survival after curative gastrectomy. The expression of c-Met in GC tissues was also positively correlated with preoperative serum CA125.

show abstract

Section: Discussionmentioning

confidence: 99%

Study on the expression of c-Met in gastric cancer and its correlation with preoperative serum tumor markers and prognosis

et al. 2022

View full text Add to dashboard Cite

show abstract

“…C-Met-targeted therapy in GC mainly includes tyrosine kinase inhibitors, monoclonal antibodies and c-Met-targeted adoptive immunotherapy. Tyrosine kinase inhibitors and monoclonal antibodies have shown obvious antitumor activity in cell and xenograft tumor models [12,[29][30][31][32], while most tumors have not achieved prominent antitumor activity in clinical trials [7,33]. Currently, only a few tumors have shown encouraging antitumor activity, especially in the treatment of NSCLC (non-small-cell lung cancer) [34,35].…”

Section: Discussionmentioning

confidence: 99%

Study on the expression of c-Met in gastric cancer and its correlation with blood tumor markers and prognosis

Zhang

Miao

Wang

et al. 2022

Preprint

View full text Add to dashboard Cite

Background: Studies have found that c-Met plays a critical role in the progression of solid tumors. This study aimed to investigate the expression of c-Met in gastric cancer (GC) and its correlation with blood tumor markers and prognosis. In order to provide a new idea and method for targeting c-Met in the treatment of GC.Methods: Ninety-seven patients who underwent GC surgery in our hospital from December 2013 to September 2015 were included in this study. The tissue microchip was constructed by paraffin cutting, including 97 GC points and 83 para-cancer points. Then, it was used for c-Met immunohistochemical staining, followed by immunological H-score. The expression of c-Met was compared with clinicopathological features, blood tumor markers (AFP, CEA, CA199, CA153, CA125, CA50) and 5-year survival. Descriptive statistics, Pearson correlation test, Kaplan-Meyer survival curve and COX regression were used for statistical analysis.Results: The high expression rate of c-Met was 64.95% (63/97) in GC tissues, and 28.92% (24/83) in para-cancer tissues. There were prominent statistical differences in the M-stage and clinicopathological stage between the low and high expression groups (P<0.05), the c-Met high expression group also had a higher M-stage and clinicopathological stage of GC. The correlation test between the c-Met H-score and CA125 was statistically significant (P=0.004), indicating a positive correlation. High c-Met expression correlated with poor overall survival (OS) for 5 years (HR=2.103, P=0.005). After the clinicopathological classification of patients, it was found that the high expression of c-Met in stage Ⅰ-Ⅱ patients was correlative with poor OS for 5 years (HR=2.486, P=0.026), while stage Ⅲ-Ⅳ patients had no statistical significance (P>0.05). Univariate and multivariate COX regression analysis showed that age, clinicopathological stage, c-Met high expression and preoperative serum AFP might be independent risk factors for survival 5 years after surgery.Conclusion: This study found that the high expression of c-Met in GC was associated with poor 5-year OS in GC patients and was an independent risk factor for 5-year survival after GC surgery. The expression of c-Met in GC was positively correlated with preoperative serum CA125.

show abstract

“…Time-resolved fluorescence-based HTRF KinEASE-TK (Cisbio, Codolet, France) was used to evaluate the RET kinase activity as previously described [ 27 ]. The reaction was performed in a 96-well plate with a kinase reaction mixture containing 0.1 μM TK-substrate biotin, 100 μM ATP, 1 ng of RET kinase (Millipore, Darmstadt, Germany), and a serial three-fold dilution of the test compound in a kinase reaction buffer (50 mM HEPES; pH 7.0, 5 mM MgCl 2 , 1 mM DTT, 0.1 mM orthovanadate, 0.01% bovine serum albumin [BSA], and 0.02% NaN 3 ).…”

Section: Methodsmentioning

confidence: 99%

Characterization of LDD-2633 as a Novel RET Kinase Inhibitor with Anti-Tumor Effects in Thyroid Cancer

et al. 2021

Self Cite

View full text Add to dashboard Cite

Rearranged during transfection (RET), a receptor tyrosine kinase, is activated by glial cell line-derived neurotrophic factor family ligands. Chromosomal rearrangement or point mutations in RET are observed in patients with papillary thyroid and medullary thyroid carcinomas. Oncogenic alteration of RET results in constitutive activation of RET activity. Therefore, inhibiting RET activity has become a target in thyroid cancer therapy. Here, the anti-tumor activity of a novel RET inhibitor was characterized in medullary thyroid carcinoma cells. The indirubin derivative LDD-2633 was tested for RET kinase inhibitory activity. In vitro, LDD-2633 showed potent inhibition of RET kinase activity, with an IC50 of 4.42 nM. The growth of TT thyroid carcinoma cells harboring an RET mutation was suppressed by LDD-2633 treatment via the proliferation suppression and the induction of apoptosis. The effects of LDD-2633 on the RET signaling pathway were examined; LDD-2633 inhibited the phosphorylation of the RET protein and the downstream molecules Shc and ERK1/2. Oral administration of 20 or 40 mg/kg of LDD-2633 induced dose-dependent suppression of TT cell xenograft tumor growth. The in vivo and in vitro experimental results supported the potential use of LDD-2633 as an anticancer drug for thyroid cancers.

show abstract

Discovery of an Indirubin Derivative as a Novel c-Met Kinase Inhibitor with In Vitro Anti-Tumor Effects

Cited by 11 publications

References 23 publications

Study on the expression of c-Met in gastric cancer and its correlation with preoperative serum tumor markers and prognosis

Study on the expression of c-Met in gastric cancer and its correlation with preoperative serum tumor markers and prognosis

Study on the expression of c-Met in gastric cancer and its correlation with blood tumor markers and prognosis

Characterization of LDD-2633 as a Novel RET Kinase Inhibitor with Anti-Tumor Effects in Thyroid Cancer

Contact Info

Product

Resources

About