A5018927031- Pharmacogenetics and Drug Metabolism
- Supramolecular Chemistry and Complexes
- Luminescence and Fluorescent Materials
- Molecular Sensors and Ion Detection
- Chemical Reaction Mechanisms
- Synthesis and Biological Evaluation
- Drug Transport and Resistance Mechanisms
- Carcinogens and Genotoxicity Assessment
- DNA Repair Mechanisms
- Cancer Treatment and Pharmacology
- Eicosanoids and Hypertension Pharmacology
- Protein Degradation and Inhibitors
- Renal cell carcinoma treatment
- Cancer Mechanisms and Therapy
- Organic Chemistry Cycloaddition Reactions
- Acute Lymphoblastic Leukemia research
- Epigenetics and DNA Methylation
- Fibroblast Growth Factor Research
- Inhalation and Respiratory Drug Delivery
- Statistical Methods in Clinical Trials
- Cancer Immunotherapy and Biomarkers
- Advanced Drug Delivery Systems
- Biochemical and Molecular Research
- Bladder and Urothelial Cancer Treatments
- Cancer, Hypoxia, and Metabolism
Arvinas (United States)
2024
Bristol-Myers Squibb (United States)
2009-2018
Applied Optimization (United States)
2015
Bristol-Myers Squibb (Germany)
2010-2014
University of Minnesota
2006-2011
Amgen (United States)
2009
Johns Hopkins University
2006-2007
Johns Hopkins Medicine
2007
University of New Orleans
2004-2005
Abstract The YAP-TEAD protein-protein interaction (PPI) is a critical event known to mediate YAP oncogenic functions downstream of the Hippo pathway. Current advanced pharmacological agents which aim at inhibiting function do so by engaging into lipid pocket TEAD. Thereby consequences direct disruption interface and TEADs remain unexplored. Here we report identification IAG933, first molecule able potently directly disrupt YAP/TAZ-TEADs PPI with suitable properties enter in clinical trial....
5011 Background: Patients with mCRPC inevitably develop resistance to available therapies, eg, novel hormonal agents (NHAs), and experience disease progression. Certain mutations that can in the ligand-binding domain (LBD; amino acids 671–920) of AR gene during treatment have been associated poor outcomes. ARV-766 is a novel, potent, orally administered PROTAC degrader targets wild-type clinically relevant LBD mutants, including most prevalent L702H, H875Y, T878A mutations. We report initial...
In a recent study, limited to South Asian Indian subjects (<i>n</i> = 12), coproporphyrin (CP) I and CPIII demonstrated properties appropriate for an organic anion-transporting polypeptide (OATP) 1B endogenous probe. The current studies were conducted in healthy volunteers of mixed ethnicities, including black, white, Hispanic subjects, better understand the utility these biomarkers broader populations. After oral administration with 600 mg rifampin, <i>AUC</i><sub>(0–24h)</sub> values 2.8-,...
The covalent conjugation of polyethylene glycol (PEG, typical MW > 10k) to therapeutic peptides and proteins is a well-established approach improve their pharmacokinetic properties diminish the potential for immunogenicity. Even though PEG generally considered biologically inert safe in animals humans, slow clearance large PEGs raises concerns about adverse effects resulting from accumulation tissues following chronic administration, particularly central nervous system. key information...
Acylfulvenes (AFs) are a class of semisynthetic agents with high toxicity toward certain tumor cells, and for one analogue, hydroxymethylacylfulvene (HMAF), clinical trials in progress. DNA alkylation by AFs, mediated bioreductive activation, is believed to contribute cytotoxicity, but the structures chemical properties corresponding adducts unknown. This study provides first structural characterization AF-specific adducts. In presence reductive enzyme, alkenal/one oxidoreductase (AOR), AF...
Selective pairing of engineering nucleosides in DNA duplexes provides a potential means to probe structurally modified bases (i.e., adducts) and address challenges associated with correlating adduct chemical structure biological impact. The current study the first example thermodynamically stable base pair that is comprised biologically relevant carcinogen−DNA synthetic nucleoside probe. O6-Benzylguanine mutagenic adduct; molecular modeling indicates novel diaminonaphthyl-derived...
Acylfulvenes comprise a family of semisynthetic natural product derivatives with potent antitumor activities. Previous studies indicated that acylfulvenes are bioactivated by NADPH-dependent alkenal/one reductase (AOR), presumably generating intermediates the capacity to alkylate cellular targets, such as DNA, proteins, and glutathione. This process is thought induce apoptosis, chemical biochemical pathways involved topics current investigation. In this study, four acylfulvene analogues were...
The goal of this study was to evaluate the pharmacokinetics, mass balance, metabolism, routes and extent elimination, safety a single oral dose <sup>14</sup>C-labeled brivanib alaninate tolerability after multiple doses in patients with advanced or metastatic solid tumors. This two-part, single-center, open-label, oral-dose (part A) followed by multiple-dose B) In part A, received [<sup>14</sup>C]brivanib B 800 mg nonradiolabeled every day. Four (two white, two black: non–small-cell lung...
Abstract Background: WNT974, a Porcupine inhibitor, has shown evidence of Wnt pathway inhibition in clinical trials. Dysregulated signaling been linked to immunotherapy resistance, suggesting WNT974 may act synergistically with checkpoint inhibitors. Spartalizumab is an αPD-1 mAb demonstrated activity solid tumors. Methods: In this Phase I, open-label trial (NCT01351103) adult pts received ± spartalizumab; here we report on the dose escalation combination. Eligible had melanoma (including...
The synthesis and binding properties of a new macrocycle is reported. host, comprised three basic pyridines, four hydrogen bond accepting carbonyls, two donating amide groups, binds mono-alkyl ammonium salts in manner that dependent on the counter-ion guest.
Acylfulvenes (AFs) are a class of antitumor agents that exert their cytotoxic effects by forming covalent adducts with biomolecules, including DNA and proteins; clinical trials ongoing for (−)-(hydroxymethyl)AF. Recently, depurinating N3-AF-deoxyadenosine (dAdo) N7-AF-deoxyguanosine (dGuo) were identified from reactions the parent compound, AF, calf thymus in presence reductase enzyme alkenal/one oxidoreductase (AOR) cofactor NADPH. We report here development structure-specific quantitative...
Brivanib [(<i>R</i>)-1-(4-(4-fluoro-2-methyl-1<i>H</i>-indol-5-yloxy)-5-methylpyrrolo[1,2,4]triazin-6-yloxy)propan-2-ol, BMS-540215] is a potent and selective dual inhibitor of vascular endothelial growth factor (VEGF) fibroblast (FGF) signaling pathways. Its alanine prodrug, brivanib alaninate [(1<i>R</i>,2<i>S</i>)-2-aminopropionic acid 2-[4-(4-fluoro-2-methyl-1<i>H</i>-indol-5-yloxy)-5-methylpyrrolo[2,1-<i>f</i>][1,2,4]triazin-6-yloxy]-1-methylethyl ester, BMS-582664], currently under...
1. Asunaprevir (ASV, BMS-650032), a highly selective and potent NS3 protease inhibitor, is currently under development for the treatment of chronic hepatic C virus infection. This study describes in vivo biotransformation humans identification metabolic enzymes ASV.2. Following single oral dose [14C]ASV to humans, majority radioactivity (>73% dose) was excreted feces with <1% recovered urine. Drug-related readily appeared circulation plasma mainly attributed ASV. A few minor metabolites were...
Brivanib alaninate, the l-alanine ester prodrug of brivanib, is currently being developed as an anticancer agent. In humans, brivanib alaninate rapidly hydrolyzed to brivanib. Prominent biotransformation pathways included oxidation and direct sulfate conjugation. A series in vitro studies were conducted identify human esterases involved hydrolysis primary cytochrome P450 sulfotransferase (SULT) enzymes metabolism was efficiently converted presence either carboxylesterase 1 or 2. Because are...
BMS-823778 is a potent and selective inhibitor of 11β-HSD1, an enzyme that regulates tissue-specific intracellular glucocorticoid metabolism compelling target for the treatment metabolic diseases. Metabolism was mediated mainly by polymorphic CYP2C19, with minor contributions from CYP3A4/5 UGT1A4. The clinical pharmacokinetics (PK) first investigated in healthy volunteers after single multiple ascending doses. rapidly absorbed oral dose, systemic exposure at steady state increased...
Acylfulvenes (AFs), a class of semisynthetic analogues the sesquiterpene natural product illudin S, are cytotoxic toward cancer cells. The minor structural changes between S and AFs translate to an improved therapeutic window in preclinical cell-based assays xenograft models. are, therefore, unique tools for addressing chemical biochemical basis selectivity. elicit responses by alkylation biological targets, including DNA. While capable direct alkylation, cytosolic reductive bioactivation...
BMS-823778 is an inhibitor of 11β-hydroxysteroid dehydrogenase type-1, and thus a potential candidate for Type 2 diabetes treatment. Here, we investigated the metabolism pharmacokinetics to understand its pharmacokinetic variations in early clinical trials.The was characterized multiple vitro assays. Pharmacokinetics were evaluated healthy volunteers, prescreened as CYP2C19 extensive metabolizers (EM) or poor (PM), with single oral dose [14 C]BMS-823778 (10 mg, 80 μCi).Three metabolites...
Aims Previous studies demonstrated direct correlation between CYP2C19 genotype and BMS‐823778 clearance in healthy volunteers. The objective of the present study was to develop a physiologically‐based pharmacokinetic (PBPK) model for use predict PK drug–drug interaction (DDI) virtual populations with multiple polymorphic genes. Methods PBPK built verified using existing clinical data. simulated significance DDI strong CYP3A4 inhibitor subjects various UGT1A4 genotypes. Results accurately...
Brivanib alaninate is an orally administered alanine prodrug of brivanib, a dual inhibitor the vascular endothelial growth factor (VEGF) and fibroblast (FGF) signaling pathways. It currently in clinical trials for treatment hepatocellular carcinoma colorectal cancer. has single asymmetric center derived from secondary alcohol. The potential chiral inversion was investigated incubations with liver subcellular fractions animals humans after oral doses brivanib alaninate. Incubations...
A pair of enantioselective, ditopic macrocycles is described; the receptors bind chiral ammonium cations in a manner that depends on stereochemistry cation as well nature its counter anion.
[reaction: see text] Three families of tris-pyridyl methanol ligands were synthesized. An analysis the Zn(2+) binding properties revealed that both steric and electronic pyridine substituents, as well nature group on tertiary alcohol oxygen, control thermodynamics kinetics complex formation.
3566 Background: Brivanib alaninate (BMS-582664, B) is an oral prodrug of BMS-540215, a dual tyrosine kinase inhibitor VEGFR and FGFR signaling pathways which are important for angiogenesis tumor growth. The recommended phase II/III dose B 800 mg daily. Methods: A two-part, open-label, single-dose study was conducted in subjects with advanced or metastatic solid tumors. Part represented the period assessment pharmacokinetics (PK), metabolism, elimination B, In part A, received single [ 14...