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Discovery of N-((1-(4-(3-(3-((6,7-Dimethoxyquinolin-3-yl)oxy)phenyl)ureido)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)propionamide (CHMFL-KIT-8140) as a Highly Potent Type II Inhibitor Capable of Inhibiting the T670I "Gatekeeper" Mutant of cKIT Kinase.
Li B, Wang A, Liu J, Qi Z, Liu X, Yu K, Wu H, Chen C, Hu C, Wang W, Wu J, Hu Z, Ye L, Zou F, Liu F, Wang B, Wang L, Ren T, Zhang S, Bai M, Zhang S, Liu J, Liu Q
(2016) J Med Chem 59: 8456-72
MeSH Terms: Amides, Animals, Cell Line, Tumor, Female, Gastrointestinal Neoplasms, Gastrointestinal Stromal Tumors, Gastrointestinal Tract, Halogenation, Humans, Methylation, Mice, Mice, Nude, Models, Molecular, Mutation, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-kit, Rats, Sprague-Dawley, Structure-Activity Relationship
Show Abstract · Added April 2, 2019
cKIT kinase inhibitors, e.g., imatinib, could induce drug-acquired mutations such as cKIT T670I that rendered drug resistance after chronic treatment. Through a type II kinase inhibitor design approach we discovered a highly potent type II cKIT kinase inhibitor compound 35 (CHMFL-KIT-8140), which potently inhibited both cKIT wt (IC50 = 33 nM) and cKIT gatekeeper T670I mutant (IC50 = 99 nM). Compound 35 displayed strong antiproliferative effect against GISTs cancer cell lines GIST-T1 (cKIT wt, GI50 = 4 nM) and GIST-5R (cKIT T670I, GI50 = 26 nM). In the cellular context it strongly inhibited c-KIT mediated signaling pathways and induced apoptosis. In the BaF3-TEL-cKIT-T670I isogenic cell inoculated xenograft mouse model, 35 exhibited dose dependent tumor growth suppression efficacy and 100 mg/kg dosage provided 47.7% tumor growth inhibition (TGI) without obvious toxicity. We believe compound 35 would be a good pharmacological tool for exploration of the cKIT-T670I mutant mediated pathology in GISTs.
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MeSH Terms
High-Resolution Mapping of RNA Polymerases Identifies Mechanisms of Sensitivity and Resistance to BET Inhibitors in t(8;21) AML.
Zhao Y, Liu Q, Acharya P, Stengel KR, Sheng Q, Zhou X, Kwak H, Fischer MA, Bradner JE, Strickland SA, Mohan SR, Savona MR, Venters BJ, Zhou MM, Lis JT, Hiebert SW
(2016) Cell Rep 16: 2003-16
MeSH Terms: Antineoplastic Agents, Azepines, Cell Line, Tumor, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, Clustered Regularly Interspaced Short Palindromic Repeats, DNA-Directed RNA Polymerases, Drug Resistance, Neoplasm, Enhancer Elements, Genetic, Gene Expression Regulation, Leukemic, High-Throughput Nucleotide Sequencing, Humans, Leukemia, Myeloid, Acute, MicroRNAs, Multigene Family, Myeloid Cell Leukemia Sequence 1 Protein, Promoter Regions, Genetic, Protein Isoforms, Proteins, Proto-Oncogene Proteins c-kit, Transcription, Genetic, Translocation, Genetic, Triazoles
Show Abstract · Added April 6, 2017
Bromodomain and extra-terminal domain (BET) family inhibitors offer an approach to treating hematological malignancies. We used precision nuclear run-on transcription sequencing (PRO-seq) to create high-resolution maps of active RNA polymerases across the genome in t(8;21) acute myeloid leukemia (AML), as these polymerases are exceptionally sensitive to BET inhibitors. PRO-seq identified over 1,400 genes showing impaired release of promoter-proximal paused RNA polymerases, including the stem cell factor receptor tyrosine kinase KIT that is mutated in t(8;21) AML. PRO-seq also identified an enhancer 3' to KIT. Chromosome conformation capture confirmed contacts between this enhancer and the KIT promoter, while CRISPRi-mediated repression of this enhancer impaired cell growth. PRO-seq also identified microRNAs, including MIR29C and MIR29B2, that target the anti-apoptotic factor MCL1 and were repressed by BET inhibitors. MCL1 protein was upregulated, and inhibition of BET proteins sensitized t(8:21)-containing cells to MCL1 inhibition, suggesting a potential mechanism of resistance to BET-inhibitor-induced cell death.
Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
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23 MeSH Terms
Transplanted murine long-term repopulating hematopoietic cells can differentiate to osteoblasts in the marrow stem cell niche.
Hofmann TJ, Otsuru S, Marino R, Rasini V, Veronesi E, Murgia A, Lahti J, Boyd K, Dominici M, Horwitz EM
(2013) Mol Ther 21: 1224-31
MeSH Terms: Animals, Bone Marrow Transplantation, Cell Differentiation, Hematopoiesis, Hematopoietic Stem Cells, Immunohistochemistry, Immunophenotyping, In Situ Hybridization, Fluorescence, Mice, Osteoblasts, Phenotype, Pilot Projects, Proto-Oncogene Proteins c-kit, Reverse Transcriptase Polymerase Chain Reaction, Stem Cell Niche
Show Abstract · Added March 7, 2014
Bone marrow transplantation (BMT) can give rise to donor-derived osteopoiesis in mice and humans; however, the source of this activity, whether a primitive osteoprogenitor or a transplantable marrow cell with dual hematopoietic and osteogenic potential, has eluded detection. To address this issue, we fractionated whole BM from mice according to cell surface immunophenotype and assayed the hematopoietic and osteopoietic potentials of the transplanted cells. Here, we show that a donor marrow cell capable of robust osteopoiesis possesses a surface phenotype of c-Kit(+) Lin(-) Sca-1(+) CD34(-/lo), identical to that of the long-term repopulating hematopoietic stem cell (LTR-HSC). Secondary BMT studies demonstrated that a single marrow cell able to contribute to hematopoietic reconstitution in primary recipients also drives robust osteopoiesis and LT hematopoiesis in secondary recipients. These findings indicate that LTR-HSC can give rise to progeny that differentiate to osteoblasts after BMT, suggesting a mechanism for prompt restoration of the osteoblastic HSC niche following BM injury, such as that induced by clinical BMT preparative regimens. An understanding of the mechanisms that regulate this differentiation potential may lead to novel treatments for disorders of bone as well as methods for preserving the integrity of endosteal hematopoietic niches.
1 Communities
1 Members
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15 MeSH Terms
Routine multiplex mutational profiling of melanomas enables enrollment in genotype-driven therapeutic trials.
Lovly CM, Dahlman KB, Fohn LE, Su Z, Dias-Santagata D, Hicks DJ, Hucks D, Berry E, Terry C, Duke M, Su Y, Sobolik-Delmaire T, Richmond A, Kelley MC, Vnencak-Jones CL, Iafrate AJ, Sosman J, Pao W
(2012) PLoS One 7: e35309
MeSH Terms: Cell Line, Tumor, Clinical Trials as Topic, DNA Mutational Analysis, Eligibility Determination, GTP-Binding Protein alpha Subunits, GTP-Binding Protein alpha Subunits, Gq-G11, Genetic Testing, Humans, Male, Melanoma, Molecular Diagnostic Techniques, Nerve Tissue Proteins, Point Mutation, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-kit, Proto-Oncogene Proteins p21(ras), Skin Neoplasms
Show Abstract · Added September 3, 2013
PURPOSE - Knowledge of tumor mutation status is becoming increasingly important for the treatment of cancer, as mutation-specific inhibitors are being developed for clinical use that target only sub-populations of patients with particular tumor genotypes. Melanoma provides a recent example of this paradigm. We report here development, validation, and implementation of an assay designed to simultaneously detect 43 common somatic point mutations in 6 genes (BRAF, NRAS, KIT, GNAQ, GNA11, and CTNNB1) potentially relevant to existing and emerging targeted therapies specifically in melanoma.
METHODS - The test utilizes the SNaPshot method (multiplex PCR, multiplex primer extension, and capillary electrophoresis) and can be performed rapidly with high sensitivity (requiring 5-10% mutant allele frequency) and minimal amounts of DNA (10-20 nanograms). The assay was validated using cell lines, fresh-frozen tissue, and formalin-fixed paraffin embedded tissue. Clinical characteristics and the impact on clinical trial enrollment were then assessed for the first 150 melanoma patients whose tumors were genotyped in the Vanderbilt molecular diagnostics lab.
RESULTS - Directing this test to a single disease, 90 of 150 (60%) melanomas from sites throughout the body harbored a mutation tested, including 57, 23, 6, 3, and 2 mutations in BRAF, NRAS, GNAQ, KIT, and CTNNB1, respectively. Among BRAF V600 mutations, 79%, 12%, 5%, and 4% were V600E, V600K, V600R, and V600M, respectively. 23 of 54 (43%) patients with mutation harboring metastatic disease were subsequently enrolled in genotype-driven trials.
CONCLUSION - We present development of a simple mutational profiling screen for clinically relevant mutations in melanoma. Adoption of this genetically-informed approach to the treatment of melanoma has already had an impact on clinical trial enrollment and prioritization of therapy for patients with the disease.
3 Communities
8 Members
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17 MeSH Terms
Bid protects the mouse hematopoietic system following hydroxyurea-induced replicative stress.
Liu Y, Aiello A, Zinkel SS
(2012) Cell Death Differ 19: 1602-12
MeSH Terms: Animals, Antigens, Ly, Antineoplastic Agents, Apoptosis, Ataxia Telangiectasia Mutated Proteins, BH3 Interacting Domain Death Agonist Protein, Cell Cycle Proteins, DNA Repair, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Hydroxyurea, Membrane Proteins, Methylcellulose, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Progenitor Cells, Nucleotidyltransferases, Oxidative Stress, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-kit
Show Abstract · Added December 5, 2013
Hematopoietic stem cells (HSCs) possess long-term self-renewal capacity and multipotent differentiative capacity, to maintain the hematopoietic system. Long-term hematopoietic homeostasis requires effective control of genotoxic damage to maintain HSC function and prevent propagation of deleterious mutations. Here we investigate the role of the BH3-only Bcl-2 family member Bid in the response of murine hematopoietic cells to long-term replicative stress induced by hydroxyurea (HU). The PI3-like serine/threonine kinase, ATR, initiates the DNA damage response (DDR) to replicative stress. The pro-apoptotic Bcl-2 family member, Bid, facilitates this response to replicative stress in hematopoietic cells, but the in vivo role of this DDR function of Bid has not been defined. Surprisingly, we demonstrate that long-term HU treatment expands wild-type myeloid progenitor cells (MPCs) and HSC-enriched Lin(-)Sca1(+)Kit(+) (LSK) cells to maintain bone marrow function as measured by long-term competitive repopulating ability. Bid-/- MPCs demonstrate increased sensitivity to HU and are depleted. Bid-/- LSK cells demonstrate increased mobilization manifest by increased Bromodeoxyuridine (BrdU) incorporation. Bid-/- MPCs and LSK cells are relatively depleted, however, and bone marrow from Bid-/- mice demonstrates decreased long-term competitive repopulating ability in both primary and secondary transplants. We thus describe a survival function of Bid in hematopoiesis in the setting of chronic replicative stress.
1 Communities
1 Members
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21 MeSH Terms
RAF265 inhibits the growth of advanced human melanoma tumors.
Su Y, Vilgelm AE, Kelley MC, Hawkins OE, Liu Y, Boyd KL, Kantrow S, Splittgerber RC, Short SP, Sobolik T, Zaja-Milatovic S, Dahlman KB, Amiri KI, Jiang A, Lu P, Shyr Y, Stuart DD, Levy S, Sosman JA, Richmond A
(2012) Clin Cancer Res 18: 2184-98
MeSH Terms: Animals, Apoptosis, Base Sequence, Cell Cycle Proteins, Cell Proliferation, Cyclin D1, Extracellular Signal-Regulated MAP Kinases, Female, Gene Expression Profiling, Humans, Imidazoles, Ki-67 Antigen, MAP Kinase Signaling System, Male, Melanoma, Mice, Mice, Nude, Mutation, Oligonucleotide Array Sequence Analysis, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-kit, Proto-Oncogene Proteins p21(ras), Pyridines, Sequence Analysis, DNA, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, bcl-X Protein
Show Abstract · Added June 14, 2013
PURPOSE - The purpose of this preclinical study was to determine the effectiveness of RAF265, a multikinase inhibitor, for treatment of human metastatic melanoma and to characterize traits associated with drug response.
EXPERIMENTAL DESIGN - Advanced metastatic melanoma tumors from 34 patients were orthotopically implanted to nude mice. Tumors that grew in mice (17 of 34) were evaluated for response to RAF265 (40 mg/kg, every day) over 30 days. The relation between patient characteristics, gene mutation profile, global gene expression profile, and RAF265 effects on tumor growth, mitogen-activated protein/extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) phosphorylation, proliferation, and apoptosis markers was evaluated.
RESULTS - Nine of the 17 tumors that successfully implanted (53%) were mutant BRAF (BRAF(V600E/K)), whereas eight of 17 (47%) tumors were BRAF wild type (BRAF(WT)). Tumor implants from 7 of 17 patients (41%) responded to RAF265 treatment with more than 50% reduction in tumor growth. Five of the 7 (71%) responders were BRAF(WT), of which 1 carried c-KIT(L576P) and another N-RAS(Q61R) mutation, while only 2 (29%) of the responding tumors were BRAF(V600E/K). Gene expression microarray data from nonimplanted tumors revealed that responders exhibited enriched expression of genes involved in cell growth, proliferation, development, cell signaling, gene expression, and cancer pathways. Although response to RAF265 did not correlate with pERK1/2 reduction, RAF265 responders did exhibit reduced pMEK1, reduced proliferation based upon reduced Ki-67, cyclin D1 and polo-like kinase1 levels, and induction of the apoptosis mediator BCL2-like 11.
CONCLUSIONS - Orthotopic implants of patient tumors in mice may predict prognosis and treatment response for melanoma patients. A subpopulation of human melanoma tumors responds to RAF265 and can be characterized by gene mutation and gene expression profiles.
©2012 AACR.
2 Communities
11 Members
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30 MeSH Terms
Comprehensive genomic analysis reveals clinically relevant molecular distinctions between thymic carcinomas and thymomas.
Girard N, Shen R, Guo T, Zakowski MF, Heguy A, Riely GJ, Huang J, Lau C, Lash AE, Ladanyi M, Viale A, Antonescu CR, Travis WD, Rusch VW, Kris MG, Pao W
(2009) Clin Cancer Res 15: 6790-9
MeSH Terms: Aged, Carcinoma, Cluster Analysis, ErbB Receptors, Female, Genomics, Humans, Immunohistochemistry, Male, Middle Aged, Mutation, Nucleic Acid Hybridization, Oligonucleotide Array Sequence Analysis, Proto-Oncogene Proteins c-kit, Signal Transduction, Thymoma, Thymus Neoplasms
Show Abstract · Added March 24, 2014
PURPOSE - Thymomas and thymic carcinomas are rare intrathoracic malignancies that can be invasive and refractory to conventional treatment. Because these tumors both originate from the thymus, they are often grouped together clinically. However, whether the underlying biology of these tumors warrants such clustering is unclear, and the optimum treatment of either entity is unknown.
EXPERIMENTAL DESIGN - All thymic tumors were profiled for mutations in genes encoding components of the EGFR and KIT signaling pathways, assessed for EGFR and KIT expression by immunohistochemistry, and analyzed by array-based comparative genomic hybridization. Previously untreated tumors were subjected to global gene expression arrays.
RESULTS - We analyzed 45 thymic tumors [thymoma, n = 38 (type A, n = 8; type B2, n = 22; type B3, n = 8); thymic carcinoma, n = 7]. One thymoma and one thymic carcinoma harbored KRAS mutations (G12A and G12V, respectively), and one thymoma had a G13V HRAS mutation. Three tumors displayed strong KIT staining. Two thymic carcinomas harbored somatic KIT mutations (V560del and H697Y). In cell viability assays, the V560del mutant was associated with similar sensitivities to imatinib and sunitinib, whereas the H697Y mutant displayed greater sensitivity to sunitinib. Genomic profiling revealed distinct differences between type A to B2 thymomas versus type B3 and thymic carcinomas. Moreover, array-based comparative genomic hybridization could readily distinguish squamous cell carcinomas of the thymus versus the lung, which can often present a diagnostic challenge.
CONCLUSIONS - Comprehensive genomic analysis suggests that thymic carcinomas are molecularly distinct from thymomas. These data have clinical, pathologic, and therapeutic implications for the treatment of thymic malignancies.
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17 MeSH Terms
Phase II study of neoadjuvant imatinib in glioblastoma: evaluation of clinical and molecular effects of the treatment.
Razis E, Selviaridis P, Labropoulos S, Norris JL, Zhu MJ, Song DD, Kalebic T, Torrens M, Kalogera-Fountzila A, Karkavelas G, Karanastasi S, Fletcher JA, Fountzilas G
(2009) Clin Cancer Res 15: 6258-66
MeSH Terms: Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Benzamides, Biomarkers, Tumor, Brain Neoplasms, Extracellular Signal-Regulated MAP Kinases, Female, Glioblastoma, Humans, Imatinib Mesylate, Ki-67 Antigen, Male, Middle Aged, Neoadjuvant Therapy, Oncogene Protein v-akt, Piperazines, Proto-Oncogene Proteins c-kit, Pyrimidines, Receptors, Platelet-Derived Growth Factor, Signal Transduction, Young Adult
Show Abstract · Added August 17, 2016
PURPOSE - Phase I-II studies indicate that imatinib is active in glioblastoma multiforme. To better understand the molecular and clinical effects of imatinib in glioblastoma multiforme, we conducted a neoadjuvant study of imatinib with pretreatment and posttreatment biopsies.
EXPERIMENTAL DESIGN - Patients underwent a computerized tomography-guided biopsy of their brain tumors. If diagnosed with glioblastoma multiforme, they were immediately treated with 7 days of imatinib 400 mg orally twice daily followed by either definitive surgery or re-biopsy. Pretreatment and posttreatment tissue specimens were tested by immunohistochemistry for Ki67 and microvessel destiny, and posttreatment specimens were analyzed for the presence of intact imatinib in tissue. Furthermore, pretreatment and posttreatment pairs were analyzed by Western blotting for activation of platelet-derived growth factor receptor, epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase/AKT, and mitogen-activated protein kinase signaling pathways. Pharmacokinetic studies were also done.
RESULTS - Twenty patients were enrolled. Median survival was 6.2 months. Intact imatinib was detected in the posttreatment tissue specimens using mass spectrometry. There was no evidence of a drug effect on proliferation, as evidenced by a change in Ki67 expression. Biochemical evidence of response, as shown by decreased activation of AKT and mitogen-activated protein kinase or increased p27 level, was detected in 4 of 11 patients with evaluable, matched pre- and post-imatinib biopsies. Two patients showed high-level EGFR activation and homozygous EGFR mutations, whereas one patient had high-level platelet-derived growth factor receptor-B activation.
CONCLUSIONS - Intact imatinib was detected in glioblastoma multiforme tissue. However, the histologic and immunoblotting evaluations suggest that glioblastoma multiforme proliferation and survival mechanisms are not substantially reduced by imatinib therapy in most patients.
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23 MeSH Terms
Deletion of Mtg16, a target of t(16;21), alters hematopoietic progenitor cell proliferation and lineage allocation.
Chyla BJ, Moreno-Miralles I, Steapleton MA, Thompson MA, Bhaskara S, Engel M, Hiebert SW
(2008) Mol Cell Biol 28: 6234-47
MeSH Terms: Anemia, Animals, Antigens, CD34, Bone Marrow Cells, Cell Lineage, Cell Proliferation, Chromosomes, Mammalian, Colony-Forming Units Assay, Female, Gene Deletion, Gene Regulatory Networks, Hematopoietic Stem Cells, Humans, Male, Megakaryocytes, Mice, Multipotent Stem Cells, Myeloid Progenitor Cells, Nuclear Proteins, Phenylhydrazines, Proto-Oncogene Proteins c-kit, Proto-Oncogene Proteins c-myc, Receptors, IgG, Time Factors, Transcription Factors, Translocation, Genetic
Show Abstract · Added August 13, 2010
While a number of DNA binding transcription factors have been identified that control hematopoietic cell fate decisions, only a limited number of transcriptional corepressors (e.g., the retinoblastoma protein [pRB] and the nuclear hormone corepressor [N-CoR]) have been linked to these functions. Here, we show that the transcriptional corepressor Mtg16 (myeloid translocation gene on chromosome 16), which is targeted by t(16;21) in acute myeloid leukemia, is required for hematopoietic progenitor cell fate decisions and for early progenitor cell proliferation. Inactivation of Mtg16 skewed early myeloid progenitor cells toward the granulocytic/macrophage lineage while reducing the numbers of megakaryocyte-erythroid progenitor cells. In addition, inactivation of Mtg16 impaired the rapid expansion of short-term stem cells, multipotent progenitor cells, and megakaryocyte-erythroid progenitor cells that is required under hematopoietic stress/emergency. This impairment appears to be a failure to proliferate rather than an induction of cell death, as expression of c-Myc, but not Bcl2, complemented the Mtg16(-/-) defect.
2 Communities
2 Members
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26 MeSH Terms
A 17 year-old man with an exon 11 mutation of CD-117 causing a gastrointestinal stromal tumor.
Bauer TM, Berlin JD
(2008) Cancer Invest 26: 182-4
MeSH Terms: Adolescent, DNA Mutational Analysis, Exons, Gastrointestinal Stromal Tumors, Humans, Male, Mutation, Proto-Oncogene Proteins c-kit
Show Abstract · Added March 20, 2014
Gastrointestinal stromal tumors (GIST) are tumors most frequently found in adults. They are often related to activating mutations in the CD-117 tyrosine kinase receptor, most commonly at exon 11. Gastrointestinal stromal tumors have been reported in children. However, until recently, there had not been reports of activating mutations in the CD-117 gene, and none have yet documented an exon 11 mutation. We report the case of a 17-year-old found to have an activating mutation in exon 11 of the CD-117 gene. This could play a role in treatment with the targeted therapeutic agent imatinib mesylate.
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8 MeSH Terms