A5036014338- Melanoma and MAPK Pathways
- Acute Myeloid Leukemia Research
- Colorectal Cancer Treatments and Studies
- Chronic Myeloid Leukemia Treatments
- Histone Deacetylase Inhibitors Research
- Chronic Lymphocytic Leukemia Research
- Cancer Mechanisms and Therapy
- Synthesis and biological activity
- Pharmacogenetics and Drug Metabolism
- PI3K/AKT/mTOR signaling in cancer
- Lung Cancer Treatments and Mutations
- Innovative Microfluidic and Catalytic Techniques Innovation
- Molecular Junctions and Nanostructures
- Cancer therapeutics and mechanisms
- Protein Tyrosine Phosphatases
- Computational Drug Discovery Methods
- Cytokine Signaling Pathways and Interactions
- HER2/EGFR in Cancer Research
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Electrochemical sensors and biosensors
- Electrochemical Analysis and Applications
- Advanced Breast Cancer Therapies
- Protein Degradation and Inhibitors
- Data Visualization and Analytics
- Lanthanide and Transition Metal Complexes
Pfizer (United States)
2020-2025
Array BioPharma (United States)
2015-2023
Nova Southeastern University
2016
University of Minnesota
2016
West Virginia University
2009-2016
University of Kentucky
2016
University at Buffalo, State University of New York
2012-2013
Dent Neurologic Institute
2012
Library of Virginia
2011
Jilin University
2009
Capping off an era marred by drug development failures and punctuated waning interest presumed intractability toward direct targeting of KRAS, new technologies strategies are aiding in the target's resurgence. As previously reported, tetrahydropyridopyrimidines were identified as irreversible covalent inhibitors KRASG12C that bind switch-II pocket KRAS make a bond to cysteine 12. Using structure-based design conjunction with focused vitro absorption, distribution, metabolism excretion...
Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated histology-agnostic efficacy in patients with fusion-positive cancers. Although responses to inhibition can be dramatic and durable, duration of response may eventually limited by acquired resistance. LOXO-195 is TKI designed overcome resistance mediated recurrent domain (solvent front xDFG) mutations identified multiple who have developed TKIs. Activity against these was confirmed enzyme cell-based assays vivo...
Species and tissue differences in the activity of three major classes esterases, carboxylesterase (CE), butyrylcholinesterase (BChE) paraoxonase (PON), were studied. Substantial species these esterases observed between mouse, rat, dog monkey human. Such must be considered when using preclinical to optimize pharmacokinetic properties ester compounds intended for human use.
ABSTRACT Binimetinib is a MEK1/2 inhibitor particularly active in cells harboring activating mutations the MAP kinase pathway, especially BRAF and NRAS . Binimetinib, combination with encorafenib, has received marketing approval several jurisdictions for treatment of patients V600E or V600K mutant melanoma. The absorption, distribution, metabolism, excretion binimetinib were evaluated by administering carbon 14–labeled 45 mg dose (containing 40 μCi radiolabeled material) to 6 healthy male...
Objectives: Pexmetinib is a novel dual inhibitor of p38 mitogen-activated protein kinase and endothelial tyrosine receptor, Tie2, under prior investigation in low or intermediate-1 risk myelodysplastic syndrome (MDS) (NCT00916227 NCT01496495). The objectives this analysis were to describe the population pharmacokinetics (popPK) pexmetinib evaluate potential covariates that may be important predictors (PK). Methods: Data from two Phase 1 healthy volunteer studies MDS patients included...
Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) suppress normal hematopoietic activity in part by enabling a pathogenic inflammatory milieu the bone marrow. In this report, we show that elevation of angiopoietin-1 myelodysplastic CD34(+) stem-like cells is associated with higher risk disease reduced overall survival MDS AML patients. Increased expression was transcriptomic signature similar to known MDS/AML cell profiles. seeking small-molecule inhibitor pathway, discovered...
This open-label, dose-finding phase Ib/II study reports the safety and activity of first combination use with BRAF inhibitor (BRAFi) encorafenib plus MEK (MEKi) binimetinib in patients V600E-mutant solid tumors.In I, recommended 2 doses (RP2D) were established (primary objective). In II, clinical at RP2D was assessed objective) BRAF-mutant metastatic colorectal cancer (mCRC), BRAFi-treated melanoma, BRAFi-naïve melanoma.A total 126 tumors enrolled (phase I: 47 patients; II: 79 patients). The...
Cytochrome P450 (P450) enzymes typically require the presence of at least cytochrome reductase (CPR) and NADPH to carry out metabolism xenobiotics. To address whether need for redox transfer proteins cofactor protein could be obviated, CYP2C9 was bonded a gold electrode through an 11-mercaptoundecanoic acid octanethiol self-assembled monolayer (SAM) which current applied. Cyclic voltammetry demonstrated direct electrochemistry enzyme fast electron between heme iron electrode. determine this...
Encorafenib is a kinase inhibitor indicated for the treatment of patients with BRAF mutant melanoma and metastatic colorectal cancer. To understand effect food coadministration proton-pump (PPI), in vitro, vivo, silico data were generated to optimize clinical dose, evaluate safety, better oral absorption process under these conditions. Study 1 evaluated on plasma pharmacokinetics, tolerability after single dose encorafenib 100 mg. 2 same end points rabeprazole (PPI perpetrator). The vitro...
Encorafenib is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma colorectal cancer, respectively, selected BRAF V600 mutations. A clinical drug–drug interaction (DDI) study was designed to evaluate effect encorafenib on rosuvastatin, sensitive substrate OATP1B1/3 and breast cancer resistance protein (BCRP), bupropion, CYP2B6 substrate. Coproporphyrin I (CP-I), an endogenous OATP1B1, measured in separate deconvolute mechanism transporter DDI....
9518 Background: The benefits of BRAF + MEK inhibition (dual combo) in pts with V600-mutant ( V600 ) melanoma are known. Preclinical data supports inhibiting CDK 4/6 and (triple to improve antitumor activity. We report safety preliminary efficacy from a phase 1b/2 study (NCT01543698) encorafenib (ENCO; selective kinase inhibitor), binimetinib (BINI; ribociclib (RIBO; inhibitor). Methods: Phase 1b this open-label, multicenter enrolled confirmed advanced solid tumors. Escalating doses RIBO 100...
In this paper, Mn12-based ordered honeycomb structures were successfully constructed from a simple solution casting process at high relative humidity through the modification of fatty acids to Mn12 clusters. Mn12−fatty acid complexes maintain typical features single-molecule magnet as confirmed by IR spectra and magnetization hysteresis studies. Investigation effects concentration, velocity humid airflow, solvent, substrate, alkyl chain length complex on morphology demonstrated wide...
Abstract Encorafenib is a potent and selective ATP competitive inhibitor of BRAF V600–mutant kinase approved for patients with BRAF‐mutant melanoma colorectal cancer. mainly metabolized by cytochrome P450 (CYP) 3A4 in vitro may be susceptible to drug–drug interactions when co‐administered CYP3A inhibitors or inducers. The primary objective was assess the impact strong posaconazole (part 1) moderate P‐gp diltiazem 2) on encorafenib pharmacokinetics healthy volunteers following single 50‐mg...
Encorafenib is a novel kinase inhibitor of BRAF V600E as well wild-type and CRAF has received approval, in combination with binimetinib, to treat or V600K mutation-positive unresectable metastatic melanoma cetuximab colorectal cancer. The absorption, distribution, metabolism excretion (ADME) encorafenib was studied by administering [14 C] (100 mg containing 90 μCi radiolabeled material) 4 healthy male subjects (NCT01436656). Following single oral 100-mg dose subjects, the overall recovery...
Electron transfer in cytochrome P450 enzymes is a fundamental process for activity. It difficult to measure electron these because under the conditions typically used they exist variety of states. Using nanotechnology-based techniques, gold conducting nanopillars were constructed an indexed array. The enzyme CYP2C9 was attached each nanopillars, and conductivity measurements made using probe atomic force microscopy constant conditions. on alone with bound substrates, substrate-effector pair,...
Abstract Background A clinical drug-drug interaction (DDI) study was designed to evaluate the effect of multiple doses modafinil, a moderate CYP3A4 inducer at 400 mg QD dose, on oral dose pharmacokinetics (PK) encorafenib and its metabolite, LHY746 binimetinib AR00426032. Methods This conducted in patients with BRAF V600-mutant advanced solid tumors. Treatment modafinil given Day 15 through 21. Encorafenib 450 45 BID were administered starting 1. PK sampling from 0 8 h 14 Exposure parameters...
Cytochrome P450 (P450) protein-protein interactions have been shown to alter their catalytic activity. Furthermore, these are isoform specific and can elicit activation, inhibition, or no effect on enzymatic Studies show that effects also dependent the protein partner cytochrome reductase (CPR) order of addition purified reconstituted enzyme systems. In this study, we use controlled immobilization P450s a gold surface gain better understanding P450-P450 between three key drug-metabolizing...
TPS3180 Background: The MAPK pathway plays a role in several key signaling and phosphorylation events that contribute to tumorigenesis. Inhibition of MEK, along with RAF kinases, has proven be successful transformative strategy for melanoma other pathway-altered tumors. However, the duration clinical benefit is limited by narrow therapeutic index, de novo acquired resistance poor brain penetration. PF-07799544 next-generation, fully penetrant MEK inhibitor. PF-07799933 an oral selective...
Mesenchymal-epithelial transition factor (MET) is a receptor tyrosine kinase that serves critical function in numerous developmental, morphogenic, and proliferative signaling pathways. If dysregulated, MET has been shown to be involved the development survival of several cancers, including non-small cell lung cancer (NSCLC), renal cancer, other epithelial tumors. Currently, clinical efficacy FDA approved inhibitors limited by on-target acquired resistance, dose-limiting toxicities, less than...
Monte Carlo simulations (MCS) present a powerful tool to evaluate candidate regimens by determining the probability of target attainment. Although these assessments have traditionally incorporated variability in pharmacokinetic (PK) parameters and MICs, consideration interstrain pharmacodynamic (PD) has been neglected. A population PK/PD model was developed for doripenem using murine thigh infection data based on 20 bacterial strains. PK were fit linear two-compartment with first-order input...
This work describes an original and simple technique for protein immobilization into nanowells, fabricated using nanopatterned array fabrication methods, while ensuring the retains normal biological activity. Nanosphere lithography was used to fabricate a nanowell with nanowells 100 nm in diameter periodicity of 500 nm. The base gold surrounding material silicon dioxide. different surface chemistries these materials were attach two self-assembled monolayers (SAM) affinities here, cytochrome...
ADAPT 5 is a powerful modeling software for population pharmacokinetic and pharmacodynamic systems analysis, but provides limited built-in functionality creating pre- post-analysis diagnostic plots. Model Evaluation Graphical Toolkit (AMGET), an external package written in the open source R programming language, was developed specifically to support efficient postprocessing of runs, as well NONMEM S-ADAPT runs. Using interactive navigational menus, users AMGET are able rapidly create...
Abstract Non-Hodgkins Lymphoma (NHL) is the second most rapidly increasing cause of cancer-related death in US, making selection appropriate combinations against B-cell lymphoma increasingly important. Our aim was to develop a pharmacodynamic (PD) model characterize interaction obatoclax and bortezomib (BTZ), which target pathways associated with acquired resistance therapies rituximab chemotherapy NHL. Primary tumor cells from patients (n=45) previously untreated relapsed/refractory...