A5076533789- Computational Drug Discovery Methods
- Lung Cancer Treatments and Mutations
- Liver physiology and pathology
- Innovative Microfluidic and Catalytic Techniques Innovation
- Neuropeptides and Animal Physiology
- Cancer Mechanisms and Therapy
- Peptidase Inhibition and Analysis
- Cancer Genomics and Diagnostics
- Colorectal Cancer Treatments and Studies
- CRISPR and Genetic Engineering
- Genetics, Bioinformatics, and Biomedical Research
- Cancer Research and Treatments
- Melanoma and MAPK Pathways
- Chromatin Remodeling and Cancer
- Cell Image Analysis Techniques
- Protein Degradation and Inhibitors
- Hepatocellular Carcinoma Treatment and Prognosis
- PI3K/AKT/mTOR signaling in cancer
- Fibroblast Growth Factor Research
- Signaling Pathways in Disease
- Diabetes Treatment and Management
- Chemical Synthesis and Analysis
- Single-cell and spatial transcriptomics
- Epigenetics and DNA Methylation
- Neuroendocrine Tumor Research Advances
Novartis (United States)
2017-2019
Foundation for Biomedical Research
2019
Tufts University
2008-2016
Arisaph Pharmaceuticals (United States)
2016
Boston University
2014
Abstract Purpose: The selective MET inhibitor capmatinib is being investigated in multiple clinical trials, both as a single agent and combination. Here, we describe the preclinical data of capmatinib, which supported biomarker strategy for rational patient selection. Experimental Design: selectivity cellular activity were assessed large screening panels. Antitumor efficacy was quantified set cell line– or patient-derived xenograft models, testing single-agent combination treatment depending...
FGF-21 is a key regulator of metabolism and potential drug candidate for the treatment type II diabetes other metabolic disorders. However, half-life active, circulating, human has recently been shown to be limited in mice monkeys by proteolytic cleavage between P171 S172. Here, we show that fibroblast activation protein enzyme responsible this proteolysis demonstrating purified FAP cleaves at site vitro, an FAP-specific inhibitor, ARI-3099, blocks activity mouse, monkey plasma prolongs...
Dipeptidyl peptidase IV (DPP-IV; E.C. 3.4.14.5), a serine protease that degrades the incretin hormones GLP-1 and GIP, is now validated target for treatment of type 2 diabetes. Dipeptide boronic acids, among first, still most potent DPP-IV inhibitors known, suffer from concern over their safety. Here we evaluate potency, in vivo efficacy, safety selected set these inhibitors. The adverse effects induced by acid-based are essentially limited to what has been observed previously non-boronic...
Bioactive peptides have evolved to optimally fulfill specific biological functions, a fact which has long attracted attention for their use as therapeutic agents. While there been some recent commercial successes fostered in part by advances large-scale peptide synthesis, development of agents significantly impeded inherent susceptibility protease degradation the bloodstream. Here we report that incorporation specially designed amino acid analogues at P1' position, directly C-terminal enzyme...
Abstract For a majority of patients with non–small cell lung cancer EGFR mutations, treatment inhibitors (EGFRi) induces clinical response. Despite this initial reduction in tumor size, residual disease persists that leads to relapse. Elucidating the preexisting biological differences between sensitive cells and surviving drug-tolerant persister deciphering how evolve response could help identify strategies improve efficacy EGFRi. In study, we tracked origins clonal evolution at high...
<div>AbstractPurpose:<p>The selective MET inhibitor capmatinib is being investigated in multiple clinical trials, both as a single agent and combination. Here, we describe the preclinical data of capmatinib, which supported biomarker strategy for rational patient selection.</p>Experimental Design:<p>The selectivity cellular activity were assessed large screening panels. Antitumor efficacy was quantified set cell line– or patient-derived xenograft models, testing...
<p>Supplementary text and figures Supplementary Figure 1 A, visualization of the "inflection point" (or EC50) "Amax" parameters that are shown in Fig. 2A. B, HGF mRNA expression (by RNA-seq) vs protein culture supernatant for 76 cancer cell lines. Cell lines with high generally led to increased levels supernatant. U87-MG IM95 labeled, because vivo efficacy data presented those models. shows a remarkably level secretion despite relatively low mRNA. C, labeled scored as hits at least 2...
<div>AbstractPurpose:<p>The selective MET inhibitor capmatinib is being investigated in multiple clinical trials, both as a single agent and combination. Here, we describe the preclinical data of capmatinib, which supported biomarker strategy for rational patient selection.</p>Experimental Design:<p>The selectivity cellular activity were assessed large screening panels. Antitumor efficacy was quantified set cell line– or patient-derived xenograft models, testing...
<p>Supplementary text and figures Supplementary Figure 1 A, visualization of the "inflection point" (or EC50) "Amax" parameters that are shown in Fig. 2A. B, HGF mRNA expression (by RNA-seq) vs protein culture supernatant for 76 cancer cell lines. Cell lines with high generally led to increased levels supernatant. U87-MG IM95 labeled, because vivo efficacy data presented those models. shows a remarkably level secretion despite relatively low mRNA. C, labeled scored as hits at least 2...
<p>Supplemental Figure S6 shows clone family UMAPs, proportion change in response to drug, and gene signature set expression at untreated acute drug treatment.</p>
<p>Supplemental Figure S3 shows Louvain clusters overlaid onto UMAP plots and contribution of cells by time point.</p>
<p>Supplemental Figure S8 shows clone family contribution at drug resistance and sensitivity to combinations.</p>
<p>Supplemental Figure S6 shows clone family UMAPs, proportion change in response to drug, and gene signature set expression at untreated acute drug treatment.</p>
<p>Supplemental Figure S5 shows distribution of barcoded clones into Louvain clusters.</p>
<p>Supplemental Figure S3 shows Louvain clusters overlaid onto UMAP plots and contribution of cells by time point.</p>
<p>Supplemental Figure S7 shows clone family gene signature set expression at drug tolerance.</p>
<p>Legends for Supplemental Figures and Tables</p>
<p>Supplemental Figure S2 shows UMAP plots, entropy analysis, quantification of barcode abundance, cell sensitivity to drug, and average gene signature set expression in sensitive vs tolerant clones.</p>
<p>Supplemental Figure S8 shows clone family contribution at drug resistance and sensitivity to combinations.</p>
<p>Legends for Supplemental Figures and Tables</p>
<p>Supplemental Tables 1 - 12</p>