Plasma and cerebrospinal fluid pharmacokinetics of MP470 in non-human primates

Baxter, Patrícia; Thompson, Patrick A.; McGuffey, Leticia; Gibson, Brian; Dauser, Robert C.; Nuchtern, Jed G.; Shi, Chongtie; Inloes, Roger; Choy, Gavin; Redkar, Sanjeev; Blaney, Susan M.

doi:10.1007/s00280-010-1380-3

Cited by 5 publications

(5 citation statements)

References 20 publications

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“…Inhibitor 33 (MP470, amuvatinib) is structurally different from most of the MET inhibitors in Chart , as it has a piperazinyl ring to deliver the aryl group into the back pocket instead of a phenoxy group . Compound 33 is reported to be a multitarget tyrosine kinase inhibitor that has demonstrated in vitro and in vivo activity against multiple validated cancer targets including mutant KIT, mutant PDGFR, mutant FLT3, MET, and RET …”

Section: Met Small Molecule Inhibitorsmentioning

confidence: 99%

Targeting Receptor Tyrosine Kinase MET in Cancer: Small Molecule Inhibitors and Clinical Progress

2013

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The HGF/MET signaling pathway is critical in mediating a wide range of normal physiological functions including embryological development, wound healing, and tissue regeneration. Aberrant activation of the pathway has frequently been found in human cancers via protein overexpression, mutation, gene amplification, and also paracrine or autocrine up-regulation. In addition, the activation of HGF/MET signaling confers resistance to the effects of cancer treatments. Therefore, inhibition of the HGF/MET signaling pathway has great potential for therapeutic intervention in cancer. Currently, there are three approaches toward modulating HGF/MET signaling in human clinical studies of cancer: anti-HGF monoclonal antibodies, MET monoclonal antibodies, and small molecule MET inhibitors. Preliminary clinical benefit from inhibition of HGF or MET has been reported. This Perspective will provide an overview of the HGF/MET signaling pathway in cancer and then will review the development of small molecule MET inhibitors and their progress in clinical applications.

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Section: Met Small Molecule Inhibitorsmentioning

confidence: 99%

Targeting Receptor Tyrosine Kinase MET in Cancer: Small Molecule Inhibitors and Clinical Progress

2013

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“…It has been reported that MP‐470 is a multi‐targeted inhibitor of the receptor tyrosine kinases Flt3, c‐Kit, Axl, c‐Met, PDGFRα/β, and c‐Ret. 29 , 30 , 31 To identify which of these purported targets are expressed in our NSCLC cell‐lines, we first investigated their expression via RT‐PCR. We found that H460 cells expressed AXL, MET , and PDGFRβ mRNA, as did A549 cells with the inclusion of PDGFRα (Figure S3A ).…”

Section: Resultsmentioning

confidence: 99%

“…To better understand the mechanism by which MP‐470 inhibits cell proliferation, we investigated the expression of its targets and the downstream signalling pathways that contribute to this effect. It has been reported that MP‐470 is a multi‐targeted inhibitor of the receptor tyrosine kinases Flt3, c‐Kit, Axl, c‐Met, PDGFRα/β, and c‐Ret 29–31 . To identify which of these purported targets are expressed in our NSCLC cell‐lines, we first investigated their expression via RT‐PCR.…”

Section: Resultsmentioning

confidence: 99%

βIII‐tubulin suppression enhances the activity of Amuvatinib to inhibit cell proliferation in c‐Met positive non‐small cell lung cancer cells

et al. 2022

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Lung cancer is one of the most common cancer types and remains a leading cause of cancer-related mortality worldwide. 1 The most common sub-type of lung cancer, non-small cell lung carcinoma (NSCLC), represents more than 80% of cases and has a dismal 5-year survival rate of less than 15%. 2 Chemotherapy remains the most effective treatment option however problems with drug resistance and toxicity present major clinical challenges. 3 Microtubules form a major component of the cell cytoskeleton and alterations in the expression of microtubule proteins are increasingly correlated with more aggressive and treatment-refractory cancers. 3 Intracellular signalling

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“…suggest that they display a higher preference for the oncogenic mutants over wild-type FLT3. (15). They are all rather nonspecific kinase inhibitors inhibiting a wide range of kinases.…”

Section: Targeting Receptor Ubiquitinationmentioning

confidence: 99%

FMS-like Tyrosine Kinase 3/FLT3: From Basic Science to Clinical Implications

Kazi

Rönnstrand

2019

Physiological Reviews

141

147

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FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is expressed almost exclusively in the hematopoietic compartment. Its ligand, FLT3 ligand (FL), induces dimerization and activation of its intrinsic tyrosine kinase activity. Activation of FLT3 leads to its autophosphorylation and initiation of several signal transduction cascades. Signaling is initiated by the recruitment of signal transduction molecules to activated FLT3 through binding to specific phosphorylated tyrosine residues in the intracellular region of FLT3. Activation of FLT3 mediates cell survival, cell proliferation, and differentiation of hematopoietic progenitor cells. It acts in synergy with several other cytokines to promote its biological effects. Deregulated FLT3 activity has been implicated in several diseases, most prominently in acute myeloid leukemia where around one-third of patients carry an activating mutant of FLT3 which drives the disease and is correlated with poor prognosis. Overactivity of FLT3 has also been implicated in autoimmune diseases, such as rheumatoid arthritis. The observation that gain-of-function mutations of FLT3 can promote leukemogenesis has stimulated the development of inhibitors that target this receptor. Many of these are in clinical trials, and some have been approved for clinical use. However, problems with acquired resistance to these inhibitors are common and, furthermore, only a fraction of patients respond to these selective treatments. This review provides a summary of our current knowledge regarding structural and functional aspects of FLT3 signaling, both under normal and pathological conditions, and discusses challenges for the future regarding the use of targeted inhibition of these pathways for the treatment of patients.

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Plasma and cerebrospinal fluid pharmacokinetics of MP470 in non-human primates

Abstract: Although CSF penetration is minimal, MP470 has demonstrated potent activity against cancer cell lines in vitro and in vivo, and further clinical investigation is warranted.

Cited by 5 publications

References 20 publications

Targeting Receptor Tyrosine Kinase MET in Cancer: Small Molecule Inhibitors and Clinical Progress

Targeting Receptor Tyrosine Kinase MET in Cancer: Small Molecule Inhibitors and Clinical Progress

βIII‐tubulin suppression enhances the activity of Amuvatinib to inhibit cell proliferation in c‐Met positive non‐small cell lung cancer cells

FMS-like Tyrosine Kinase 3/FLT3: From Basic Science to Clinical Implications

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