An Introduction and Overview of RON Receptor Tyrosine Kinase Signaling

Hunt, Brian G.; Fox, Levi H.; Davis, James N.; Jones, Angelle; Lu, Zhixin; Waltz, Susan E.

doi:10.3390/genes14020517

Cited by 6 publications

(3 citation statements)

References 116 publications

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“…We were pleased to find that compound 13 displayed inhibition of only 5 kinases below 50% POC at 1 mM ATP. RON kinase was one of the affected enzymes, and this was not surprising knowing that RON is from the same family as MET and very closely related . More importantly, the cellular inhibition of VEGFR-2 was measured due to its associated dose limiting cardiovascular side effects as mentioned earlier .…”

Section: Resultsmentioning

confidence: 89%

“…RON kinase was one of the affected enzymes, and this was not surprising knowing that RON is from the same family as MET and very closely related. 32 More importantly, the cellular inhibition of VEGFR-2 was measured due to its associated dose limiting cardiovascular side effects as mentioned earlier. 20 While cabozantinib and glesatinib gave cellular IC 50 values of 2 and 172 nM, respectively, compound 13 showed exquisite selectivity against VEGFR-2 with an IC 50 value of greater than 5000 nM.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Discovery of Pyrazolopyrazines as Selective, Potent, and Mutant-Active MET Inhibitors with Intracranial Efficacy

Bumpers,

Pipal,

Benz-Weeden

et al. 2024

J. Med. Chem.

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Mesenchymal-epithelial transition factor (MET) is a receptor tyrosine kinase that serves a critical function in numerous developmental, morphogenic, and proliferative signaling pathways. If dysregulated, MET has been shown to be involved in the development and survival of several cancers, including non-small cell lung cancer (NSCLC), renal cancer, and other epithelial tumors. Currently, the clinical efficacy of FDA approved MET inhibitors is limited by on-target acquired resistance, dose-limiting toxicities, and less than optimal efficacy against brain metastasis. Therefore, there is still an unmet medical need for the development of MET inhibitors to address these issues. Herein we report the application of structure-based design for the discovery and development of a novel class of brain-penetrant MET inhibitors with enhanced activity against clinically relevant mutations and improved selectivity. Compound 13 with a MET D1228N cell line IC50 value of 23 nM showed good efficacy in an intracranial tumor model and increased the median overall survival of the animals to 100% when dosed orally at 100 mg/kg daily for 21 days.

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Section: Resultsmentioning

confidence: 89%

Section: ■ Results and Discussionmentioning

confidence: 99%

Discovery of Pyrazolopyrazines as Selective, Potent, and Mutant-Active MET Inhibitors with Intracranial Efficacy

Bumpers,

Pipal,

Benz-Weeden

et al. 2024

J. Med. Chem.

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“… 16 Recepteur d’Origine Nantais (RON) is a receptor tyrosine kinase of the MET receptor family that is canonically involved in mediating growth, promoting wound healing and inflammatory signaling. 17 Type II IFNs (IFN-γ) is a pro-inflammatory cytokine that regulate early hematopoiesis. 18 It also has antiviral activity and can affect innate immunity.…”

Section: Introductionmentioning

confidence: 99%

CC16 as an Inflammatory Biomarker in Induced Sputum Reflects Chronic Obstructive Pulmonary Disease (COPD) Severity

Chen¹,

Xu²,

He³

et al. 2023

COPD

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The progression of an abnormal inflammatory response plays a crucial role in the lung function decline of chronic obstructive pulmonary disease (COPD) patients. Compared to serum biomarkers, inflammatory biomarkers in induced sputum would be a more reliable reflection of inflammatory processes in the airways. Patients and Methods: A total of 102 COPD participants were divided into a mild-to-moderate group (FEV1%pred≥ 50%, n=57) and a severe-to-very-severe group (FEV1%pred<50%, n=45). We measured a series of inflammatory biomarkers in induced sputum and analyzed their association with lung function and SGRQ in COPD patients. To evaluate the relationship between inflammatory biomarkers and the inflammatory phenotype, we also analyzed the correlation between biomarkers and airway eosinophilic phenotype. Results: We found increased mRNA levels of MMP9, LTB4R, and A1AR and decreased levels of CC16 mRNA in induced sputum in the severe-to-very-severe group. After adjustment for age, sex and other biomarkers, CC16 mRNA expression was positively associated with FEV1%pred (r=0.516, p=0.004) and negatively correlated with SGRQ scores (r=−0.3538, p=0.043). As previously known, decreased CC16 was related to the migration and aggregation of eosinophils in airway. It was also found that CC16 had a moderate negative correlation with the eosinophilic inflammation in airway (r=−0.363, p=0.045) in our COPD patients. Conclusion: Low CC16 mRNA expression levels in induced sputum were associated with low FEV1%pred and a high SGRQ score in COPD patients. Sputum CC16 as a potential biomarker for predicting COPD severity in clinical practice might attribute to the involvement of CC16 in airway eosinophilic inflammation.

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