A5084750823- PI3K/AKT/mTOR signaling in cancer
- HER2/EGFR in Cancer Research
- Cancer Mechanisms and Therapy
- Cancer Treatment and Pharmacology
- Chronic Myeloid Leukemia Treatments
- Acute Myeloid Leukemia Research
- Enzyme function and inhibition
- Monoclonal and Polyclonal Antibodies Research
- Nuclear Receptors and Signaling
- Multiple Myeloma Research and Treatments
- Lung Cancer Treatments and Mutations
- Microtubule and mitosis dynamics
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Protein Kinase Regulation and GTPase Signaling
- Cancer therapeutics and mechanisms
- Steroid Chemistry and Biochemistry
- Synthesis and Reactivity of Sulfur-Containing Compounds
- Mast cells and histamine
- Organic Chemistry Synthesis Methods
- Quinazolinone synthesis and applications
- Histone Deacetylase Inhibitors Research
- Protein Degradation and Inhibitors
- Toxin Mechanisms and Immunotoxins
- Signaling Pathways in Disease
- Catalytic C–H Functionalization Methods
Pfizer (United States)
2015-2023
Nationwide Children's Hospital
2011
Abstract We show that two commonly occurring epidermal growth factor receptor (EGFR) somatic mutations, L858R and an in-frame deletion mutant, Del(746-750), exhibit distinct enzymatic properties relative to wild-type EGFR are differentially sensitive erlotinib. Kinetic analysis of the purified intracellular domains Del(746-750) reveals both mutants active but a higher KM for ATP lower Ki erlotinib receptor. When expressed in NR6 cells, cell line does not express or other ErbB receptors,...
Abstract The phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway is frequently activated in human cancers, and mTOR a clinically validated target. forms two distinct multiprotein complexes, mTORC1 mTORC2, which regulate cell growth, metabolism, proliferation, survival. Rapamycin its analogues partially inhibit through allosteric binding to mTORC1, but not have shown clinical utility certain cancers. Here, we report the preclinical characterization of OSI-027, selective potent dual inhibitor...
OSI-930 is a novel inhibitor of the receptor tyrosine kinases Kit and kinase insert domain (KDR), which currently being evaluated in clinical studies. selectively inhibits KDR with similar potency intact cells also these targets vivo following oral dosing. We have investigated relationships between observed cell-based assays vitro, plasma exposure levels achieved dosing, time course target inhibition vivo, antitumor activity tumor xenograft models. In mutant Kit-expressing HMC-1 model,...
Targeted treatment of solid or liquid tumors with antibody-drug conjugates (ADCs) can lead to promising clinical benefit. The aim the study is investigate combination regimens auristatin-based ADCs in preclinical models cancer.An anti-5T4 antibody conjugate (5T4-ADC) and auristatin payloads were combined dual PI3K/mTOR catalytic site inhibitor PF-05212384 (PF-384) taxanes a panel tumor cell lines. Drug interactions vitro evaluated using viability assays, apoptosis induction,...
Mortality due to acute myeloid leukemia (AML) remains high, and the management of relapsed or refractory AML continues be therapeutically challenging. The reapproval Mylotarg, an anti-CD33-calicheamicin antibody-drug conjugate (ADC), has provided a proof concept for ADC-based therapeutic AML. Several other ADCs have since entered clinical development AML, but met with limited success. We sought develop next-generation ADC wide index (TI) that overcomes shortcomings previous generations...
This letter describes a series of small molecule inhibitors IGF-1R with unique time-dependent binding kinetics and slow off-rates. Structure-activity structure-kinetic relationships were elucidated guided further optimizations within the series, culminating in compound 2. With an dissociative half-life (t 1/2) >100 h, 2 demonstrated significant extended PD effects conjunction tumor growth inhibition xenograft models at remarkably low intermittent dose, which correlated observed vitro...
A high-throughput chemiluminescence and ELISA-based biochemical assay to identify mTORC1/mTORC2 kinase inhibitors is described. These mTOR complexes were isolated from HeLa whole cell lysate using antibodies in-well immunoprecipitation. The integrity purity of the mTORC1 mTORC2 immunocomplexes confirmed by western blotting. Full-length recombinant 4E-BP1 was used as a substrate catalytic activity measured detection p4E-BP1 [T37/46] method. performance this that can be dual in 384-well format
Abstract The PI3K/AKT/mTOR pathway is frequently activated in many human cancers and mTOR has been clinically validated as an effective anti-cancer target by rapamycin analogs such CCI-779, RAD001 AP23573. We discovered OSI-027, a potent selective small molecule kinase inhibitor that inhibits both mTORC1 mTORC2 unlike its inhibit only mTORC1. profiled several cancer cell lines to compare the mechanistic functional effects of OSI-027. Rapamycin completely inhibited phosphorylation S6...
Abstract Targeted treatment with antibody-drug conjugates (ADCs) can lead to dramatic regressions of solid tumors; combination therapies the ADCs that could potentially help achieve long-term disease control remain largely unexplored. The aim study is investigate most promising regimens auristatin-based in preclinical models cancer. A tool ADC, an anti-5T4 antibody conjugate (5T4-ADC) and permeable auristatin analogs were combined dual PI3K/mTOR catalytic site inhibitor PF-05212384 (PF-384)...
Abstract DNA targeting drugs represent one of cornerstones anti-cancer therapy for both hematologic and solid tumor indications. Low potency anti-DNA compounds (e.g. platins, anthracyclines) are included in many standard-of-care (SOC) regimens, however their modest activity overall toxicity profiles limit therapeutic potential. To increase the window DNA-damaging agents, high with enhanced anti-tumor have been delivered to tumors as payloads modalities such antibody-drug conjugates (ADCs)....
<div>Abstract<p>OSI-930 is a novel inhibitor of the receptor tyrosine kinases Kit and kinase insert domain (KDR), which currently being evaluated in clinical studies. OSI-930 selectively inhibits KDR with similar potency intact cells also these targets <i>in vivo</i> following oral dosing. We have investigated relationships between observed cell-based assays vitro</i>, plasma exposure levels achieved dosing, time course target inhibition vivo</i>,...
Supplementary Figures 1-3 from OSI-930: A Novel Selective Inhibitor of Kit and Kinase Insert Domain Receptor Tyrosine Kinases with Antitumor Activity in Mouse Xenograft Models
Supplementary Figures 1-3 from OSI-930: A Novel Selective Inhibitor of Kit and Kinase Insert Domain Receptor Tyrosine Kinases with Antitumor Activity in Mouse Xenograft Models
Supplementary Figure Legends from OSI-930: A Novel Selective Inhibitor of Kit and Kinase Insert Domain Receptor Tyrosine Kinases with Antitumor Activity in Mouse Xenograft Models
Supplementary Figure Legends from OSI-930: A Novel Selective Inhibitor of Kit and Kinase Insert Domain Receptor Tyrosine Kinases with Antitumor Activity in Mouse Xenograft Models
<div>Abstract<p>OSI-930 is a novel inhibitor of the receptor tyrosine kinases Kit and kinase insert domain (KDR), which currently being evaluated in clinical studies. OSI-930 selectively inhibits KDR with similar potency intact cells also these targets <i>in vivo</i> following oral dosing. We have investigated relationships between observed cell-based assays vitro</i>, plasma exposure levels achieved dosing, time course target inhibition vivo</i>,...
<p>Supplementary Methods to complete the information for cellular assays in vitro and protein identification by mass spectrometry. The file also contains legends supplementary figures S1-S6 tables S1-S3.</p>