A5086704967- Chronic Myeloid Leukemia Treatments
- Chronic Lymphocytic Leukemia Research
- HER2/EGFR in Cancer Research
- PI3K/AKT/mTOR signaling in cancer
- Cancer Treatment and Pharmacology
- Eosinophilic Disorders and Syndromes
- Bone Metabolism and Diseases
- RNA Interference and Gene Delivery
- Microtubule and mitosis dynamics
- Bone health and treatments
- Quinazolinone synthesis and applications
- Metabolism, Diabetes, and Cancer
- Growth Hormone and Insulin-like Growth Factors
- Chemical Synthesis and Analysis
- Angiogenesis and VEGF in Cancer
- Orthopedic Infections and Treatments
- Biopolymer Synthesis and Applications
- Mast cells and histamine
- Bone fractures and treatments
- Monoclonal and Polyclonal Antibodies Research
- Cytokine Signaling Pathways and Interactions
- Orthopaedic implants and arthroplasty
- Click Chemistry and Applications
- Histone Deacetylase Inhibitors Research
- Colorectal Cancer Treatments and Studies
Yale University
2017-2024
Albert Einstein College of Medicine
2024
Montefiore Medical Center
2024
Teikyo University
2024
Bristol-Myers Squibb (United States)
2010-2023
Pain and Rehabilitation Medicine
2022
Columbia University
2004-2015
Columbia University Irving Medical Center
2009-2015
Center for Orthopaedics
2005-2015
Johns Hopkins University
1997-2010
Resistance to the ABL kinase inhibitor imatinib (STI571 or Gleevec) in chronic myeloid leukemia (CML) occurs through selection for tumor cells harboring BCR-ABL domain point mutations that interfere with drug binding. Crystallographic studies predict most imatinib-resistant mutants should remain sensitive inhibitors bind less stringent conformational requirements. BMS-354825 is an orally bioavailable two-log increased potency relative retains activity against 14 of 15 mutants. prolongs...
A series of substituted 2-(aminopyridyl)- and 2-(aminopyrimidinyl)thiazole-5-carboxamides was identified as potent Src/Abl kinase inhibitors with excellent antiproliferative activity against hematological solid tumor cell lines. Compound 13 orally active in a K562 xenograft model chronic myelogenous leukemia (CML), demonstrating complete regressions low toxicity at multiple dose levels. On the basis its robust vivo favorable pharmacokinetic profile, selected for additional characterization...
Abstract Imatinib, a Bcr-Abl tyrosine kinase inhibitor, is highly effective therapy for patients with chronic myelogenous leukemia (CML). Despite durable responses in most phase patients, relapses have been observed and are much more prevalent advanced disease. The common mechanism of acquired imatinib resistance has traced to domain mutations decreased sensitivity. Thus, alternate inhibitors that activity against imatinib-resistant mutants would be useful who relapse on therapy. Two such...
Abstract Activating mutations of the activation loop KIT are associated with certain human neoplasms, including majority patients systemic mast cell disorders, as well cases seminoma, acute myelogenous leukemia (AML), and gastrointestinal stromal tumors (GISTs). The small-molecule tyrosine kinase inhibitor imatinib mesylate is a potent wild-type (WT) mutant isoforms has become standard care for treating metastatic GIST. However, involving codon D816 that typically found in AML, mastocytosis,...
Abstract Src family kinases (SFK) are currently being investigated as targets for treatment strategies in various cancers. The novel SFK/Abl inhibitor, dasatinib (BMS-354825), is a promising therapeutic agent with oral bioavailability. Dasatinib has been shown to inhibit growth of Bcr-Abl–dependent chronic myeloid leukemia xenografts nude mice. also have activity against cultured human prostate and breast cancer cells. However, the molecular mechanism by which acts on epithelial tumor cells...
Structural studies suggest that most point mutations in the BCR-ABL kinase domain cause resistance to ABL inhibitor imatinib by impairing flexibility of domain, restricting its ability adopt inactive conformation required for optimal binding, rather than directly interfering with drug contact residues. BMS-354825, currently clinical development imatinib-resistant chronic myelogenous leukemia, is a dual SRC/ABL binds both active and conformation. To examine potential role conformational...
It is generally believed that shutting down the kinase activity of BCR-ABL by imatinib will completely inhibit its functions, leading to inactivation downstream signaling pathways and cure disease. Imatinib highly effective at treating human Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia (CML) in phase but not Ph(+) B cell acute lymphoblastic (B-ALL) CML blast crisis. We find SRC kinases activated remain fully active imatinib-treated mouse leukemic cells, suggesting does...
Abstract Sarcomas are rare malignant mesenchymal tumors for which there limited treatment options. One potential molecular target sarcoma is the Src tyrosine kinase. Dasatinib (BMS-354825), a small-molecule inhibitor of kinase activity, promising cancer therapeutic agent with p.o. bioavailability. exhibits antitumor effects in cultured human cell lines derived from epithelial tumors, including prostate and lung carcinomas. However, action dasatinib mesenchymally has yet to be shown. Based on...
Abstract Mutations of the epidermal growth factor receptor (EGFR) selectively activate Akt and signal transducer activator transcription (STAT) pathways that are important in lung cancer cell survival. Src family kinases can cooperate with tyrosine to through downstream molecules, such as phosphatidylinositol 3-kinase/PTEN/Akt STATs. Based on importance EGFR signaling cancer, known cooperation between proteins, evidence elevated activity human cancers, we evaluated effectiveness a novel...
The insulin-like growth factor I receptor (IGF-IR) is a transmembrane tyrosine kinase that essential to and development also thought provide survival signal for the maintenance of transformed phenotype. There has been increasing interest in further understanding role IGF-I signaling cancer developing antagonists therapeutic application. We describe herein novel animal model involves transgenic expression fusion constitutively activated by homodimerization. Transgenic mice expressed showed...
Abstract The insulin-like growth factor receptor (IGF-IR) and insulin are either overactivated and/or overexpressed in a wide range of tumor types contribute to tumorigenicity, proliferation, metastasis, drug resistance. Here, we show that BMS-554417, novel small molecule developed as an inhibitor IGF-IR, inhibits IGF-IR kinase activity proliferation vitro, reduces xenograft size vivo. In series carcinoma cell lines, the IC50 for ranged from 120 nmol/L (Colo205) >8.5 μmol/L (OV202)....
Tau is a microtubule (MT)-stabilizing protein that altered in Alzheimer's disease (AD) and other tauopathies. It hypothesized the hyperphosphorylated, conformationally altered, multimeric forms of tau lead to disruption MT stability; however, direct evidence lacking vivo . In this study, an stable isotope-mass spectrometric technique was used measure turnover, or dynamicity, MTs brains living animals. We demonstrated age-dependent increase dynamics two different transgenic mouse models, 3xTg...
Abstract Overexpression and enhanced activity of insulin-like growth factor-I receptor (IGF-IR) in diverse tumor types make it an attractive target for cancer therapy. BMS-536924 is a potent small molecule inhibitor IGF-IR, which shows antitumor multiple models, including sarcoma. To facilitate the development IGF-IR inhibitors as therapy, identification biomarkers selecting patients most likely to derive clinical benefit needed. do so, 28 sarcoma neuroblastoma cell lines were screened vitro...
Abstract Activating epidermal growth factor receptor (EGFR) mutations are common in many cancers including glioblastoma. However, clinical responses to EGFR inhibitors infrequent and short-lived. We show that the Src family kinases (SFK) Fyn effectors of oncogenic signaling, enhancing invasion tumor cell survival vivo. Expression a constitutively active mutant, EGFRvIII, resulted activating phosphorylation physical association with Fyn, promoting motility. Gene silencing limited EGFR-...
High throughput screening identified 2-acetamido-thiazolylthio acetic ester 1 as an inhibitor of cyclin-dependent kinase 2 (CDK2). Because this compound is inactive in cells and unstable plasma, we have stabilized it to metabolic hydrolysis by replacing the moiety with a 5-ethyl-substituted oxazole 14. Combinatorial parallel synthesis provided rapid analysis structure-activity relationship (SAR) for these inhibitors CDK2, over 100 analogues IC(50) values 1-10 nM range were rapidly prepared....
Abstract Purpose: Chronic myeloid leukemia (CML) is caused by reciprocal translocation between chromosomes 9 and 22, forming BCR-ABL, a constitutively activated tyrosine kinase. Imatinib mesylate, selective inhibitor of represents current frontline therapy for CML; however, emerging evidence suggests that drug resistance to imatinib may limit its long-term success. To improve treatment options, dasatinib (BMS-354825) was developed as novel, oral, multi-targeted kinase BCR-ABL SRC family...
Compound 3 (BMS-536924), a novel small-molecule inhibitor of the insulin-like growth factor receptor kinase with equal potency against insulin is described. The in vitro and vivo biological activity this interesting compound also reported.
Abnormal migration and proliferation of vascular smooth muscle cells (VSMCs) are key events in the pathogenesis restenosis that undermine long-term benefit widely performed balloon angioplasty stenting procedures. Platelet-derived growth factor (PDGF) is a potent mitogen motogen for VSMCs known to play prominent role intimal accumulation cells. In this study, we analyzed effects novel protein tyrosine kinase inhibitor, BMS-354825 (dasatinib), on PDGF-stimulated VSMCs. an orally bioavailable...
Abstract Elevated levels of Src kinase expression have been found in a variety human epithelial cancers. Most notably colon cancer, elevated correlates with malignant potential and is also associated metastatic disease. Dasatinib (BMS-354825) novel, orally active, multi-targeted inhibitor that targets family kinases currently under clinical evaluation for the treatment solid tumors. However, effects dasatinib on tumors are not fully understood. We show concentrations inhibit activity do...