ReviewLeukemia2013
Targeting the KIT activating switch control pocket: a novel mechanism to inhibit neoplastic mast cell proliferation and mast cell activation.
Review in Leukemia, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
18 citing papers in PubMed, 38 citations in OpenAlex.
- Single-cell analysis unveils activation of mast cells in colorectal cancer microenvironment.Cell & bioscience · 2023Article
- Inhibition of KIT Tyrosine Kinase Activity: Two Decades After the First Approval.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2021Article
- Ripretinib for the treatment of advanced gastrointestinal stromal tumor.Therapeutic advances in gastroenterology · 2021Review
- Preclinical human models and emerging therapeutics for advanced systemic mastocytosis.Haematologica · 2018Review
- Mast Cell Activation Syndrome.Clinical reviews in allergy & immunology · 2018Review
- The KIT and PDGFRA switch-control inhibitor DCC-2618 blocks growth and survival of multiple neoplastic cell types in advanced mastocytosis.Haematologica · 2018Article
- High infiltration of mast cells positive to tryptase predicts worse outcome following resection of colorectal liver metastases.BMC cancer · 2015Article
- Targeting mast cells in gastric cancer with special reference to bone metastases.World journal of gastroenterology · 2015Review
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- Possible biological and translational significance of mast cells density in colorectal cancer.World journal of gastroenterology · 2014Review
- Mastocytosis associated with a rare germline KIT K509I mutation displays a well-differentiated mast cell phenotype.The Journal of allergy and clinical immunology · 2014Article
- Functional deregulation of KIT: link to mast cell proliferative diseases and other neoplasms.Immunology and allergy clinics of North America · 2014Review
- c-Kit expression, angiogenesis, and grading in canine mast cell tumour: a unique model to study c-Kit driven human malignancies.BioMed research international · 2014Article
- KIT GNNK splice variants: expression in systemic mastocytosis and influence on the activating potential of the D816V mutation in mast cells.Experimental hematology · 2013Article
- A novel KIT-deficient mouse mast cell model for the examination of human KIT-mediated activation responses.Journal of immunological methods · 2013Article
- Mast cell activation syndrome: a review.Current allergy and asthma reports · 2013Review
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
Activating mutations in the receptor tyrosine kinase KIT, most notably KIT D816V, are commonly observed in patients with systemic mastocytosis. Thus, inhibition of KIT has been a major focus for treatment of this disorder. Here we investigated a novel approach to such inhibition. Utilizing rational drug design, we targeted the switch pocket (SP) of KIT, which regulates its catalytic conformation. Two SP inhibitors thus identified, DP-2976 and DP-4851, were examined for effects on neoplastic mast cell proliferation and mast cell activation. Autophosphorylation of both wild-type and, where also examined, KIT D816V activation was blocked by these compounds in transfected 293T cells, HMC 1.1 and 1.2 human mast cell lines, and in CD34(+)-derived human mast cells activated by stem cell factor (SCF). Both inhibitors induced apoptosis in the neoplastic mast cell lines and reduced survival of primary bone marrow mast cells from patients with mastocytosis. Moreover, the SP inhibitors more selectively blocked SCF potentiation of FcɛRI-mediated degranulation. Overall, SP inhibitors represent an innovative mechanism of KIT inhibition whose dual suppression of KIT D816V neoplastic mast cell proliferation and SCF-enhanced mast cell activation may provide significant therapeutic benefits.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.