A5043332165- HER2/EGFR in Cancer Research
- Monoclonal and Polyclonal Antibodies Research
- Chemical Reactions and Isotopes
- Chemical synthesis and alkaloids
- Synthesis and Biological Evaluation
- Chemical Synthesis and Analysis
- Click Chemistry and Applications
- Cell Adhesion Molecules Research
- Alkaloids: synthesis and pharmacology
- Cancer Treatment and Pharmacology
- Cancer therapeutics and mechanisms
- Cancer Cells and Metastasis
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Drug Transport and Resistance Mechanisms
- Pharmacogenetics and Drug Metabolism
- Acute Myeloid Leukemia Research
- Neuroscience and Neuropharmacology Research
- CAR-T cell therapy research
- Synthesis and Catalytic Reactions
- Chemical Reaction Mechanisms
- Gastric Cancer Management and Outcomes
- Traditional and Medicinal Uses of Annonaceae
- Synthetic Organic Chemistry Methods
- Glycosylation and Glycoproteins Research
Novartis (United States)
2025
Pfizer (United States)
2015-2024
National Heart Lung and Blood Institute
2005-2021
United States Department of Veterans Affairs
2021
Connecticut Sea Grant
2021
University Hospital of the West Indies
2018
Great Ormond Street Hospital
2018
University College Hospital
2018
University College London
2018
Emory University
2017
Replacement of the central, para-substituted fluorophenyl ring in γ-secretase inhibitor 1 (BMS-708,163) withthe bicyclo[1.1.1]pentane motif led to discovery compound 3, an equipotent enzyme with significant improvements passive permeability and aqueous solubility. The modified biopharmaceutical properties 3 translated into excellent oral absorption characteristics (∼4-fold ↑ Cmax AUC values relative 1) a mouse model inhibition. In addition, SAR studies other replacements indicate intrinsic...
Antibody-drug conjugates (ADC) are emerging as clinically effective therapy. We hypothesized that cancers treated with ADCs would acquire resistance mechanisms unique to immunoconjugate therapy and changing ADC components may overcome resistance. Breast cancer cell lines were exposed multiple cycles of anti-Her2 trastuzumab-maytansinoid (TM-ADC) at IC80 concentrations followed by recovery. The resistant cells, 361-TM JIMT1-TM, characterized cytotoxicity, proteomic, transcriptional, other...
The degree of stability antibody-drug linkers in systemic circulation, and the rate their intracellular processing within target cancer cells are among key factors determining efficacy conjugates (ADC) vivo Previous studies demonstrated susceptibility cleavable linkers, as well auristatin-based payloads, to enzymatic cleavage rodent plasma. Here, we identify Carboxylesterase 1C enzyme responsible for extracellular hydrolysis valine-citrulline-p-aminocarbamate (VC-PABC)-based mouse We further...
Peroxisome proliferator-activated receptor gamma (PPARG) is a master transcriptional regulator of adipocyte differentiation and canonical target antidiabetic thiazolidinedione medications. In rare families, loss-of-function (LOF) mutations in PPARG are known to cosegregate with lipodystrophy insulin resistance; the general population, common P12A variant associated decreased risk type 2 diabetes (T2D). Whether how variants defects influence T2D population remains undetermined. By sequencing...
PTK7 is a tumor-initiating cell antigen, which can be targeted with an antibody-drug conjugate to confer sustained tumor regressions.
Auristatins, synthetic analogues of the antineoplastic natural product Dolastatin 10, are ultrapotent cytotoxic microtubule inhibitors that clinically used as payloads in antibody-drug conjugates (ADCs). The design and synthesis several new auristatin with N-terminal modifications include amino acids α,α-disubstituted carbon atoms described, including discovery our lead auristatin, PF-06380101. This modification peptide structure is unprecedented led to excellent potencies tumor cell...
Significance Combinatorial synthesis via DNA encoded library (DEL) has evolved as a technology of great importance in drug discovery. However, the idiosyncratic aqueous, dilute, DNA-sensitive parameters and infinitesimal scale this system present new challenges for traditional organic reactions. A detailed protocol aiding transition from reactions to with DNA-bound molecules was developed using tactical combination kinetic analysis reaction screening. As an example, venerable Giese addition...
Trop-2, also known as TACSTD2, EGP-1, GA733-1, and M1S1, is frequently expressed on a variety of human carcinomas, its expression often associated with poor prognosis the diseases. However, it present epithelium several normal tissues. A comprehensively designed Trop-2-targeting antibody-drug conjugate (ADC), balancing both efficacy toxicity, therefore necessary to achieve clinical utility. To this end, we developed cleavable Trop-2 ADC (RN927C) using site-specific transglutaminase-mediated...
A metabolism-based approach toward the optimization of a series N-arylsulfonamide-based γ-secretase inhibitors is reported. The lead cyclohexyl analogue 6 suffered from extensive oxidation on cycloalkyl motif by cytochrome P450 3A4, translating into poor human liver microsomal stability. Knowledge metabolic pathways triggered structure-activity relationship study aimed at lowering lipophilicity through introduction polarity. This effort led to several tetrahydropyran and tetrahydrofuran...
Transcriptomic studies in clinical research are essential tools for deciphering the functional elements of genome and unraveling underlying disease mechanisms. Various technologies have been developed to deduce quantify transcriptome including hybridization sequencing-based approaches. Recently, high density exon microarrays successfully employed detecting differentially expressed genes alternative splicing events biomarker discovery diagnostics. The field transcriptomics is currently being...
In humans, vWF levels predict the risk of myocardial infarction and thrombosis; however, factors that influence are not completely understood. Recent genome-wide association studies (GWAS) have identified syntaxin-binding protein 5 (STXBP5) as a candidate gene linked to changes in plasma levels, though functional relationship between STXBP5 is unknown. We hypothesized inhibits endothelial cell exocytosis. found expressed human cells colocalizes with interacts syntaxin 4. reduction increased...
Abstract Antibody–drug conjugates (ADC) represent a promising therapeutic modality for the clinical management of cancer. We sought to develop novel ADC that targets 5T4, an oncofetal antigen expressed on tumor-initiating cells (TIC), which comprise most aggressive cell population in tumor. optimized anti-5T4 (A1mcMMAF) by sulfydryl-based conjugation humanized A1 antibody tubulin inhibitor monomethylauristatin F (MMAF) via maleimidocaproyl linker. A1mcMMAF exhibited potent vivo antitumor...
Abstract The study of rare variants may enhance our understanding the genetic determinants metabolome. Here, we analyze association between 217 plasma metabolites and exome on Illumina HumanExome Beadchip in 2,076 participants Framingham Heart Study, with replication 1,528 Atherosclerosis Risk Communities Study. We identify an GMPS xanthosine using single variant analysis associations HAL histidine, PAH phenylalanine, UPB1 ureidopropionate gene-based tests ( P <5 × 10 −8 meta-analysis),...
As part of our efforts to develop new classes tubulin inhibitor payloads for antibody-drug conjugate (ADC) programs, we developed a tubulysin ADC that demonstrated excellent in vitro activity but suffered from rapid metabolism critical acetate ester. A two-pronged strategy was employed address this metabolism. First, the hydrolytically labile ester replaced by carbamate functional group resulting more stable retained potency cellular assays. Second, site-specific conjugation order design...
A novel α7 nAChR agonist, 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (24, CP-810,123), has been identified as a potential treatment for cognitive deficits associated with psychiatric or neurological conditions including schizophrenia and Alzheimer's disease. Compound 24 is potent selective compound excellent pharmaceutical properties. In rodent, the displays high oral bioavailability brain penetration affording levels of receptor occupancy in vivo efficacy auditory...