Patrick J. O’Hearn
A5064740552- Fibroblast Growth Factor Research
- Eosinophilic Disorders and Syndromes
- Kruppel-like factors research
- Cancer, Hypoxia, and Metabolism
- Epigenetics and DNA Methylation
- Trace Elements in Health
- Drug Transport and Resistance Mechanisms
- Chemical Synthesis and Analysis
- Multiple Myeloma Research and Treatments
- Tuberculosis Research and Epidemiology
- Peroxisome Proliferator-Activated Receptors
- Pharmaceutical studies and practices
- PI3K/AKT/mTOR signaling in cancer
- Bioactive Compounds and Antitumor Agents
- Plant biochemistry and biosynthesis
- Cancer therapeutics and mechanisms
- Chronic Lymphocytic Leukemia Research
- Adenosine and Purinergic Signaling
- Phytochemical compounds biological activities
- Monoclonal and Polyclonal Antibodies Research
- Cancer, Lipids, and Metabolism
- Computational Drug Discovery Methods
- Cancer Genomics and Diagnostics
Relay Therapeutics (United States)
2023-2024
Sage Therapeutics (United States)
2021
Broad Institute
2019-2020
Infinity Pharmaceuticals (United States)
2012-2016
Abstract Oncogenic activation of fibroblast growth factor receptor 2 (FGFR2) drives multiple cancers and represents a broad therapeutic opportunity, yet selective targeting FGFR2 has not been achieved. Although the clinical efficacy pan-FGFR inhibitors (pan-FGFRi) validates driver status in fusion–positive intrahepatic cholangiocarcinoma, their benefit is limited by incomplete target coverage due to FGFR1- FGFR4-mediated toxicities (hyperphosphatemia diarrhea, respectively) emergence...
Fibroblast growth factor receptor (FGFR) kinase inhibitors have been shown to be effective in the treatment of intrahepatic cholangiocarcinoma and other advanced solid tumors harboring FGFR2 alterations, but toxicity these drugs frequently leads dose reduction or interruption such that maximum efficacy cannot achieved. The most common adverse effects are hyperphosphatemia caused by FGFR1 inhibition diarrhea due FGFR4 inhibition, as current therapies not selective among FGFRs. Designing has...
Optimization of isoquinolinone PI3K inhibitors led to the discovery a potent inhibitor PI3K-γ (26 or IPI-549) with >100-fold selectivity over other lipid and protein kinases. IPI-549 demonstrates favorable pharmacokinetic properties robust inhibition mediated neutrophil migration in vivo is currently Phase 1 clinical evaluation subjects advanced solid tumors.
Misregulation of protein translation plays a critical role in human cancer pathogenesis at many levels. Silvestrol, cyclopenta[b]benzofuran natural product, blocks the initiation step by interfering with assembly eIF4F complex. Silvestrol has complex chemical structure whose functional group requirements have not been systematically investigated. Moreover, silvestrol limited development potential due to poor druglike properties. Herein, we sought develop practical synthesis key intermediates...
ABSTRACT Anti-cancer uses of non-oncology drugs have been found on occasion, but such discoveries serendipitous and rare. We sought to create a public resource containing the growth inhibitory activity 4,518 tested across 578 human cancer cell lines. To accomplish this, we used PRISM, which involves drug treatment molecularly barcoded lines in pools. Relative barcode abundance following thus reflects line viability. that an unexpectedly large number selectively inhibited subsets Moreover,...
Abstract FGFR2 fusions, amplifications, and mutations are oncogenic drivers that occur across multiple tumor types. Clinical efficacy observed with pan-FGFR inhibitors has validated the driver status of in fusion-positive intrahepatic cholangiocarcinoma (ICC), however, FGFR1-mediated toxicities (hyperphosphatemia, tissue mineralization) emergence on-target resistance limit inhibitors. To overcome these limitations, we designed RLY-4008, a potent highly selective, inhibitor. Despite...
Abstract Fatty acid synthase (FASN) is a key enzyme responsible for fatty acids synthesis de novo in mammals. Overexpression of FASN common many cancers including prostate, breast and colon cancer elevated expression has been linked with poor prognosis reduced disease-free survival. Experiments RNAi small molecule inhibitors suggest that metabolic oncogene an important role tumor growth survival appealing target therapy. However, studies utilizing like orlistat C75 have confounded by the...
<div>Abstract<p>Oncogenic activation of fibroblast growth factor receptor 2 (FGFR2) drives multiple cancers and represents a broad therapeutic opportunity, yet selective targeting FGFR2 has not been achieved. Although the clinical efficacy pan-FGFR inhibitors (pan-FGFRi) validates <i>FGFR2</i> driver status in fusion–positive intrahepatic cholangiocarcinoma, their benefit is limited by incomplete target coverage due to FGFR1- FGFR4-mediated toxicities...
<p>ReFocus entry criteria</p>
<p>ReFocus entry criteria</p>
<p>three references cited in supplementary data</p>
<p>Supplementary Figure 1. RLY-4008 is an irreversible inhibitor of FGFR2.</p>
<p>Supplementary Figure 1. RLY-4008 is an irreversible inhibitor of FGFR2.</p>
<p>Supplementary Figure 2. Treatment with RLY-4008 is well-tolerated and leads to dose-dependent inhibition of FGFR2 tumor regression in multiple FGFR2-altered models.</p>
<div>Abstract<p>Oncogenic activation of fibroblast growth factor receptor 2 (FGFR2) drives multiple cancers and represents a broad therapeutic opportunity, yet selective targeting FGFR2 has not been achieved. While the clinical efficacy pan-FGFR inhibitors (pan-FGFRi) validates driver status in fusion-positive intrahepatic cholangiocarcinoma, their benefit is limited by incomplete target coverage due to FGFR1- FGFR4-mediated toxicities (hyperphosphatemia diarrhea) emergence...
<p>Supplementary Figure 2. Treatment with RLY-4008 is well-tolerated and leads to dose-dependent inhibition of FGFR2 tumor regression in multiple FGFR2-altered models.</p>
<p>three references cited in supplementary data</p>