A5004778927- Lung Cancer Treatments and Mutations
- Chronic Myeloid Leukemia Treatments
- Cancer therapeutics and mechanisms
- PI3K/AKT/mTOR signaling in cancer
- Lung Cancer Research Studies
- Chronic Lymphocytic Leukemia Research
- HER2/EGFR in Cancer Research
- Click Chemistry and Applications
- Eosinophilic Disorders and Syndromes
- Quinazolinone synthesis and applications
- Cancer Mechanisms and Therapy
- Metabolism, Diabetes, and Cancer
- Lymphoma Diagnosis and Treatment
- Diet, Metabolism, and Disease
- Diet and metabolism studies
- Cytokine Signaling Pathways and Interactions
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Colorectal Cancer Treatments and Studies
- Systemic Lupus Erythematosus Research
- Gastrointestinal Tumor Research and Treatment
- Protein Degradation and Inhibitors
- Autoimmune and Inflammatory Disorders
- Dyeing and Modifying Textile Fibers
- Acute Ischemic Stroke Management
- Gastric Cancer Management and Outcomes
Ariadne Diagnostics (United States)
2006-2023
Mackay Memorial Hospital
2023
Takeda (United States)
2021-2022
National Taiwan University Hospital
2020-2022
China Medical University
2014-2021
Taipei Veterans General Hospital
2018
Taiwan Food and Drug Administration
2014
China Medical University Hospital
2014
Ministry of Health and Welfare
2014
Qihe People's Hospital
2013
In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within ALK domain have emerged as a major resistance mechanism to both first- and second-generation inhibitors. This report describes design synthesis series 2,4-diarylaminopyrimidine-based potent selective inhibitors culminating in identification investigational clinical candidate brigatinib. A unique structural...
In the treatment of chronic myeloid leukemia (CML) with BCR-ABL kinase inhibitors, T315I gatekeeper mutant has emerged as resistant to all currently approved agents. This report describes structure-guided design a novel series potent pan-inhibitors BCR-ABL, including mutation. A key structural feature is carbon-carbon triple bond linker which skirts increased bulk Ile315 side chain. Extensive SAR studies led discovery development candidate 20g (AP24534), inhibited activity both native and...
Abstract Purpose: Non–small cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK+) typically become resistant to the first-generation anaplastic lymphoma kinase (ALK) tyrosine inhibitor (TKI) crizotinib through development of secondary resistance mutations in or disease progression brain. Mutations that confer second-generation TKIs ceritinib and alectinib have also been identified. Here, we report structure first comprehensive preclinical evaluation next-generation TKI...
The BCR‐ABL inhibitor imatinib has revolutionized the treatment of chronic myeloid leukemia. However, drug resistance caused by kinase domain mutations necessitated development new mutation‐resistant inhibitors, most recently against T315I gatekeeper residue mutation. Ponatinib (AP24534) inhibits both native and mutant BCR‐ABL, including T315I, acting as a pan‐BCR‐ABL inhibitor. Here, we undertook combined crystallographic structure–activity relationship analysis on ponatinib to understand...
Most EGFR exon 20 insertion (EGFRex20ins) driver mutations in non-small cell lung cancer (NSCLC) are insensitive to approved tyrosine kinase inhibitors (TKI). To address the limitations of existing therapies targeting EGFR-mutated NSCLC, mobocertinib (TAK-788), a novel irreversible TKI, was specifically designed potently inhibit oncogenic variants containing activating EGFRex20ins with selectivity over wild-type EGFR. The vitro and vivo activity evaluated engineered patient-derived models...
Background and purpose Inflammatory processes including autoimmune diseases which ignite endothelial dysfunction atherosclerosis may promote development of cardiovascular ischaemic stroke. This study aimed to evaluate whether multiple sclerosis ( MS ) increases stroke risk. Methods A national insurance claim data set 22 million enrollees in Taiwan was used identify 1174 patients with 4696 randomly selected age‐ gender‐matched controls from 1 January 1997 31 December 2010. Both cohorts were...
Background: Although advance care planning discussions are increasingly accepted worldwide, their ideal timing is uncertain and cultural factors may pertain. Aim: To evaluate affecting initiation of for adult patients in Japan Taiwan. Design: Mixed-methods questionnaire survey to quantitatively determine percentages willing initiate at four stages illness trajectory ranging from healthy undeniably ill, identify qualitative perceptions underlying preferred timing. Setting/participants:...
Aim This study explored the effect of a moderate (90 g/d) low-carbohydrate diet (LCD) in type 2 diabetes patients over 18 months. Methods Ninety-two poorly controlled aged 20–80 years with HbA1c ≥7.5% (58 mmol/mol) previous three months were randomly assigned to 90 g/d LCD r traditional diabetic (TDD). The primary outcomes glycaemic control status and change medication score (MES). secondary lipid profiles, small, dense low-density lipoprotein (sdLDL), serum creatinine, microalbuminuria...
A novel series of potent dual Src/Abl kinase inhibitors based on a 9-(arenethenyl)purine core has been identified. Unlike traditional targeting the active enzyme conformation, these bind to inactive, DFG-out conformation both kinases. Extensive SAR studies led discovery and orally bioavailable inhibitors, some which demonstrated in vivo efficacy. Once-daily oral administration inhibitor 9i (AP24226) significantly prolonged survival mice injected intravenously with wild type Bcr-Abl...
Abstract In non-small cell lung cancer (NSCLC), multiple classes of activating mutations have been identified in EGFR and HER2 that vary widely their sensitivity to available tyrosine kinase inhibitors (TKIs). Erlotinib, gefitinib, afatinib are approved for use patients with the most common forms (ie, exon 19 deletions or L858R substitutions). However, no TKIs activated by any other mutation, including 20 insertions uncommon substitutions, class mutation (including insertions). As inhibition...
In the treatment of non-small cell lung cancer (NSCLC), patients harboring exon 20 insertion mutations in epidermal growth factor receptor (EGFR) gene have few effective therapies because this subset mutants is generally resistant to most currently approved EGFR inhibitors. This report describes structure-guided design a novel series potent, irreversible inhibitors mutations, including V769_D770insASV and D770_N771insSVD mutants. Extensive structure-activity relationship (SAR) studies led...
Bcr-Abl is the oncogenic protein tyrosine kinase responsible for chronic myeloid leukemia (CML). Treatment of disease with imatinib (Gleevec) often results in drug resistance via mutations at advanced phases disease, which has necessitated development new mutation-resistant inhibitors, notably against T315I gatekeeper mutation. As part our efforts to discover such mutation resistant Abl we have focused on optimizing purine template leading discovery potent DFG-in and DFG-out series...
Abstract Activating gene rearrangements of anaplastic lymphoma kinase (ALK) have been identified in large cell (ALCL; NPM-ALK) and non-small lung cancer (NSCLC; EML4-ALK). The dual Met/ALK inhibitor PF-02341066 (PF1066) has demonstrated promising clinical activity against tumors carrying activating ALK (Kwak ASCO 2009: #3509) validating as a therapeutic target. Previously, AP26113 was novel, potent, orally bioavailable with selectivity over related receptor tyrosine family members IGF-1R...
Abstract Several studies suggested a relationship between stress and related mental illnesses, such as depression osteoporosis. However, it was unclear whether patients with post‐traumatic disorder (PTSD) were at risk of developing osteoporosis in later life. In this study, 6,041 PTSD 24,164 age‐ or sex‐matched controls enrolled 2002 2009 our study followed up to the end 2011. Cases identified during follow‐up. Patients had an elevated likelihood (HR: 2.66, 95% CI [1.91, 3.71]) life compared...
Mutation in the ABL kinase domain is principal mechanism of imatinib resistance patients with chronic myelogenous leukaemia. The second generation BCR/ABL inhibitors nilotinib and dasatinib effectively inhibit most variants, but are ineffective against gatekeeper mutant, T315I. Gatekeeper mutation activates by stabilizing hydrophobic spine. Here, we describe that rationally designed compound AP24163 can native mutants kinase. Structural modelling suggests affects flexibility P-loop...
Abstract Introduction: GIST is the most common sarcoma of GI tract, with cases driven by activating mutations in KIT Ex11 or Ex9. Prognosis poor for patients whose tumors progress following first-line (1L) imatinib treatment, despite availability 3 approved drugs (sunitinib [2L], regorafenib [3L], ripretinib [4L]). In patients, resistance secondary KIT, nearly all occurring either ATP binding pocket (Ex13/14) activation loop (Ex17/18). No drug has potent activity against both classes and...
Abstract Phosphorus, despite its abundance in the human body, is rarely found drug molecules, with clinical utility limited to a few phosphonic or bisphosponic acid-based medicines and several phosphonate phosphate-containing prodrugs. Concerns about poor cell penetration, low oral bioavailability, biological instability have application of these functional classes design. In our efforts discover pharmaceuticals novel functionality, we introduced neutral, stable phosphine oxide moiety as...
summary . Antibodies to hepatitis C virus (HCV) may decrease or disappear after viral clearance in treated spontaneously resolved infection. We evaluated the usefulness of serial antibody assays predicting antiviral treatment responses. One hundred and four chronic patients who received 24 weeks interferon ribavirin combination therapy were assayed with a third generation enzyme immunoassay anti‐HCV. The mean titre anti‐HCV decreased by more than 50% (from 89.5 ± 10.8 43.6 17.5) at 48...
Abstract Background: EGFR activating mutations are observed in 10-50% of NSCLC patients. Although the common (L858R [L] and exon 19 deletions [D]) initially sensitive to first-, second-, third-generation inhibitors (e.g., erlotinib [1G], afatinib [2G], osimertinib [3G], respectively), on-target resistance is a substantial percentage patients, with T790M (T) C797S (C) most frequently (post-1G/2G post-3G, respectively). Furthermore, mutational heterogeneity can increase during treatment...
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