A5067726260- Lung Cancer Treatments and Mutations
- Cancer therapeutics and mechanisms
- Retinoids in leukemia and cellular processes
- Lung Cancer Research Studies
- Synthetic Organic Chemistry Methods
- Asymmetric Synthesis and Catalysis
- Protein Degradation and Inhibitors
- Estrogen and related hormone effects
- Click Chemistry and Applications
- Oxidative Organic Chemistry Reactions
- Monoclonal and Polyclonal Antibodies Research
- Cyclopropane Reaction Mechanisms
- Cancer Mechanisms and Therapy
- Peroxisome Proliferator-Activated Receptors
- Immune Response and Inflammation
- Colorectal Cancer Treatments and Studies
- Catalytic Alkyne Reactions
- Marine Sponges and Natural Products
- Cancer Treatment and Pharmacology
- Gastric Cancer Management and Outcomes
- Porphyrin and Phthalocyanine Chemistry
- Ubiquitin and proteasome pathways
- Chemical Synthesis and Analysis
- Synthesis of Organic Compounds
- Organic Chemistry Cycloaddition Reactions
Genomics Institute of the Novartis Research Foundation
2013-2023
John Jay College of Criminal Justice
2023
Odyssey Therapeutics (United States)
2022
Japanese Foundation For Cancer Research
2014
Massachusetts General Hospital
2014
Harvard University
2014
Ligand Pharmaceuticals (United States)
2002-2005
Eli Lilly (United States)
2003-2004
Aix-Marseille Université
1997-2001
Laboratoire de Synthèse Organique
1994-2000
Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to the ALK tyrosine inhibitor (TKI) crizotinib. Herein, we report first preclinical evaluation of next-generation TKI, ceritinib (LDK378), in setting crizotinib resistance. An interrogation vitro and vivo models acquired crizotinib, including lines established from biopsies patients with crizotinib-resistant NSCLC, revealed that potently overcomes mutations. In...
The synthesis, preclinical profile, and in vivo efficacy rat xenograft models of the novel selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) described as well rational design strategy employed to overcome development deficiencies first generation ALK 4 (TAE684). Compound is currently phase 1 2 clinical trials with substantial antitumor activity being observed ALK-positive cancer patients.
ALK (anaplastic lymphoma kinase) is an RTK (receptor tyrosine of the IRK (insulin receptor superfamily, which share YXXXYY autophosphorylation motif within their A-loops (activation loops). A common activation and regulatory mechanism believed to exist for members this superfamily typified by IGF1RK (insulin-like growth factor kinase-1). Chromosomal translocations involving were first identified in anaplastic large-cell lymphoma, a subtype non-Hodgkin's where aberrant fusion kinase domain...
Abstract Non–small cell lung cancer patients carrying oncogenic EGFR mutations initially respond to EGFR-targeted therapy, but later elicit minimal response due dose-limiting toxicities and acquired resistance. EGF816 is a novel, irreversible mutant-selective inhibitor that specifically targets EGFR-activating arising de novo upon resistance acquisition, while sparing wild-type (WT) EGFR. potently inhibited the most common L858R, Ex19del, T790M in vitro, which translated into strong tumor...
Over the past decade, first and second generation EGFR inhibitors have significantly improved outcomes for lung cancer patients with activating mutations in EGFR. However, both resistance through a secondary T790M mutation at gatekeeper residue dose-limiting toxicities from wild-type (WT) inhibition ultimately limit full potential of these therapies to control mutant EGFR-driven tumors new are urgently needed. Herein, we describe our approach toward discovery 47 (EGF816, nazartinib), novel,...
NOD2 (nucleotide-binding oligomerization domain-containing protein 2) is an internal pattern recognition receptor that recognizes bacterial peptidoglycan and stimulates host immune responses. Dysfunction of pathway has been associated with a number autoinflammatory disorders. To date, direct inhibitors have not described due to technical challenges targeting the oligomeric complex. Receptor interacting kinase 2 (RIPK2) intracellular serine/threonine/tyrosine kinase, key signaling partner,...
There is growing interest in therapeutic intervention that targets disease-relevant RNAs using small molecules. While there have been some successes RNA-targeted small-molecule discovery, a deeper understanding of structure–activity relationships pursuing these has remained elusive. One the best-studied tertiary-structured theophylline aptamer, which binds with high affinity and selectivity. Although not drug target, this aptamer had many applications, especially pertaining to genetic...
Specific retinoid X receptor (RXR) agonists, such as LG100268 (LG268), and the thiazolidinedione (TZD) PPARγ rosiglitazone, produce insulin sensitization in rodent models of resistance type 2 diabetes. In sharp contrast to TZDs that significant increases body weight gain, RXR agonists reduce gain food consumption. Unfortunately, also suppress thyroid hormone axis generally hypertriglyceridemia. Heterodimer-selective modulators have been identified that, rodents, retain metabolic benefits...
Thrombopoietin (Tpo) is a glycoprotein growth factor that supports hematopoietic stem cell survival and expansion the principal regulator of megakaryocyte differentiation. Several small, nonpeptidyl molecules have been identified as selective human Tpo receptor (hTpoR) agonists. To understand how small molecule mimic SB394725 interacts activates hTpoR, we performed domain swap mutagenesis studies. The results suggest specifically with extracellular juxtamembrane region (JMR) transmembrane...
Previous data have shown that RXR-selective agonists (e.g., 3 and 4) are insulin sensitizers in rodent models of non-insulin-dependent diabetes mellitus (NIDDM). Unfortunately, they also produce dramatic increases triglycerides profound suppression the thyroid hormone axis. Here we describe design synthesis new RXR modulators retain insulin-sensitizing activity but substantially reduced side effects. These molecules bind selectively with high affinity to and, unlike agonists, do not activate...
The use of allenes as proelectrophiles in Pd-catalyzed reaction provides a facile entry to macrocarbocycles, macrolactones, and macrolactams. Remarkably, medium-sized rings, notoriously the most difficult generate, are produced excellent yields, even preference more easily formed ring sizes when both feasible (see example below).
Lewis acid mediated addition of 1,8-bis(trimethylsilyl)octa-2,6-diene (BISTRO) 1 to succinic anhydride led spirolactone 2 [(±)-6,9-divinyl-1-oxaspiro[4.4]nonan-2-one]. Methoxycarbonylation followed by stereoselective alkylation various benzocyclobutenes afforded the substituted benzocyclobutene steroid precursors 5. Thermolysis 5 gave rise steroids (±)-6 with a trans-anti-cis configuration in five steps and highly manner. Modifications sequence allowed preparation (±)-11 trans-anti-trans...
Inappropriate activation of endosomal TLR7 and TLR8 occurs in several autoimmune diseases, particular systemic lupus erythematosus (SLE). Herein, the development a antagonist competition assay its application for hit generation dual TLR7/8 antagonists are reported. The structure-guided optimization pyridone 3 using this biochemical combination with cellular cocrystal structural data resulted identification highly potent selective (27) vivo efficacy. two key steps were (i) core morph guided...
Retinoid X receptor:peroxisome proliferative-activated receptor (RXR:PPAR) heterodimers play a critical role in the regulation of glucose (RXR/PPARgamma) and lipid metabolism (RXR/PPARalpha). Previously, we described concise structure-activity relationship study selective RXR modulators possessing (2E,4E,6Z)-3-methyl-7-(3,5-dialkyl-6-alkoxyphenyl)-octa-2,4,6-trienoic acid scaffold. These studies were focused on 2-position alkoxy side chain. We describe here design synthesis novel series same...
Abstract A c-MET/ALK kinase inhibitor crizotinib has demonstrated significant activity in lung cancer patients with EML4-ALK clinical studies. However relapse (or acquired resistance) also been reported. We have developed resistant tumor models and used the to evaluate ALK LDK378. LDK378 is a potent selective that does not cross react c-MET. In mouse xenograft model derived from EML4-ALK+ cell line NCI-H2228, caused complete regression when dosed orally at 25 mg/kg/day. After bearing animals...