LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models

Yan, S. Betty; Peek, Victoria L.; Ajamie, Rose T.; Buchanan, Sean G.; Graff, Jeremy R.; Heidler, Steven A.; Hui, Yu‐Hua; Huss, Karen; Konicek, Bruce W.; Manro, Jason R.; Shih, Chuan; Stewart, Julie; Stewart, Trent R.; Stout, Stephanie; Uhlik, Mark; Um, Suzane L.; Wang, Yong; Wu, Wenjuan; Yan, Lei; Yang, Wenjun; Zhong, Buqing; Walgren, Richard A.

doi:10.1007/s10637-012-9912-9

Cited by 141 publications

(142 citation statements)

References 37 publications

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“…LY2801653 has little or no inhibitory activity against KDR, and treatment was shown to induce vessel normalization in the U-87MG xenograft tumor (13). In this H441 orthotopic model, LY2801653 treatment resulted in significant reduction of VEGF level in the tumors.…”

Section: Discussionmentioning

confidence: 86%

“…On the basis of the lack of high HGF expression in H441 cells and due to the fact that mouse HGF is not recognized by human MET, the MET signaling in H441 cells would appear to principally function in a ligandindependent manner. This constitutive activation is most likely the result of MET gene amplification (13).…”

Section: Discussionmentioning

confidence: 99%

“…The levels of p-MET (Y1349) in lysate from cells or tumor tissues were measured with the Meso Scale Discovery (MSD) ELISA assay (#K151DLD-1, MSD), as described previously (13). For HGF (#DHG00, R&D), VEGF (#DEG00, R&D), and FGF2 ELISA (#DFB50, R&D), 20 mg of protein of each sample was loaded per well in duplicate.…”

Section: Elisa Assaymentioning

confidence: 99%

“…MET gene amplification analysis of H441 cells by FISH revealed that approximately 75% of the cells harbored 3 to 5 copies of the MET gene (13). No MET mutation was observed in H441 cells based on the Broad Institute Cancer Cell Line Encyclopedia database.…”

Section: Expression Of Met In Human Nsclc Specimensmentioning

confidence: 99%

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Inhibition of Tumor Growth and Metastasis in Non–Small Cell Lung Cancer by LY2801653, an Inhibitor of Several Oncokinases, Including MET

Credille

et al. 2013

Clinical Cancer Research

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Purpose: Lung cancer is the leading cause of cancer-related death worldwide. Sustained activation, overexpression, or mutation of the MET pathway is associated with a poor prognosis in a variety of tumors, including non-small cell lung cancer (NSCLC), implicating the MET pathway as a potential therapeutic target for lung cancer. Previously, we reported on the development of LY2801653: a novel, orally bioavailable oncokinase inhibitor with MET as one of its targets. Here, we discuss the evaluation of LY2801653 in both preclinical in vitro and in vivo NSCLC models.Experimental Design/Results: Treatment with LY2801653 showed tumor growth inhibition in tumor cell lines and patient-derived tumor xenograft models as a single agent (37.4%-90.0% inhibition) or when used in combination with cisplatin, gemcitabine, or erlotinib (66.5%-86.3% inhibition). Mechanistic studies showed that treatment with LY2801653 inhibited the constitutive activation of MET pathway signaling and resulted in inhibition of NCI-H441 cell proliferation, anchorage-independent growth, migration, and invasion. These in vitro findings were confirmed in the H441 orthotopic model where LY2801653 treatment significantly inhibited both primary tumor growth (87.9% inhibition) and metastasis (64.5% inhibition of lymph node and 67.7% inhibition of chest wall). Tumor-bearing animals treated with LY2801653 had a significantly greater survival time (87% increase compared with the vehicle-treated mice). In the MET-independent NCI-H1299 orthotopic model, treatment with LY2801653 showed a significant inhibition of primary tumor growth but not metastasis.Conclusions: Collectively, these results support clinical evaluation of LY2801653 in NSCLCs and suggest that differences in the MET activation of tumors may be predictive of response.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Elisa Assaymentioning

confidence: 99%

Section: Expression Of Met In Human Nsclc Specimensmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of Tumor Growth and Metastasis in Non–Small Cell Lung Cancer by LY2801653, an Inhibitor of Several Oncokinases, Including MET

Credille

et al. 2013

Clinical Cancer Research

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“…MSP-treatment resulted in significant upregulation of surface levels of PD-L1 and CD80 on macrophages, whereas PD-L2 remained unchanged and CD86 was downregulated (Figure 1d,e). MSP-RON-mediated upregulation of CD80 and PD-L1 was blocked when either of two RON-selective kinase inhibitors, BMS777607 or merestinib (LY2801653), 36,45 were added (Figure 1f). …”

Section: Resultsmentioning

confidence: 99%

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

et al. 2018

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The advent of immune checkpoint blockade as a new strategy for immunotherapy has changed the outlook for many aggressive cancers. Although complete tumor eradication is attainable in some cases, durable clinical responses are observed only in a small fraction of patients, underlining urgent need for improvement. We previously showed that RON, a receptor tyrosine kinase expressed in macrophages, suppresses antitumor immune responses, and facilitates progression and metastasis of breast cancer. Here, we investigated the molecular changes that occur downstream of RON activation in macrophages, and whether inhibition of RON can cooperate with checkpoint immunotherapy to eradicate tumors. Activation of RON by its ligand, MSP, altered the gene expression profile of macrophages drastically and upregulated surface levels of CD80 and PD-L1, ligands for T-cell checkpoint receptors CTLA-4 and PD-1. Genetic deletion or pharmacological inhibition of RON in combination with anti-CTLA-4, but not with anti-PD-1, resulted in improved clinical responses against orthotopically transplanted tumors compared to single-agent treatment groups, resulting in complete tumor eradication in 46% of the animals. Positive responses to therapy were associated with higher levels of T-cell activation markers and tumor-infiltrating lymphocytes. Importantly, co-inhibition of RON and anti-CTLA-4 was also effective in clearing metastatic breast cancer cells in lungs, resulting in clinical responses in nearly 60% of the mice. These findings suggest that RON inhibition can be a novel approach to potentiate responses to checkpoint immunotherapy in breast cancer.

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Blood retinal barrier and ocular pharmacokinetics: Considerations for the development of oncology drugs

Williamson

Reddy

2021

Biopharm & Drug Disp

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Tyrosine kinase inhibitors (TKIs) are an example of targeted drug therapy to treat cancer while minimizing damage to healthy tissue. In contrast to traditional oncology drugs, the toxicity profile of targeted therapies is less well understood and can include severe ocular adverse events, which are among the most common toxicity reported by these therapeutics. Inhibition of Mer receptor tyrosine kinase (MERTK) promotes innate tumor immunity by decreasing M2‐macrophage polarization and efferocytosis. This mechanism offers the opportunity for targeted immunotherapy to treat cancer; however, the ocular expression of MERTK increases the difficulty for developing a targeted drug due to toxicity concerns. In this article we review the pharmacokinetic (PK) parameters and in vitro absorption, distribution, metabolism, and excretion (ADME) assays available to evaluate ocular disposition and assess the relationship between clinical PK and reported ocular events for TKIs to allow backtranslation to preclinical models. Understanding the ocular disposition in the context of PK and safety remains an evolving area and is likely to be a key aspect of developing safe and efficacious oncology drugs, devoid of ocular toxicity.

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LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models

Cited by 141 publications

References 37 publications

Inhibition of Tumor Growth and Metastasis in Non–Small Cell Lung Cancer by LY2801653, an Inhibitor of Several Oncokinases, Including MET

Inhibition of Tumor Growth and Metastasis in Non–Small Cell Lung Cancer by LY2801653, an Inhibitor of Several Oncokinases, Including MET

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

Blood retinal barrier and ocular pharmacokinetics: Considerations for the development of oncology drugs

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