A5039844178- Melanoma and MAPK Pathways
- PARP inhibition in cancer therapy
- Lung Cancer Treatments and Mutations
- Kruppel-like factors research
- Fibroblast Growth Factor Research
- Cancer-related Molecular Pathways
- Computational Drug Discovery Methods
- Cancer Mechanisms and Therapy
- Monoclonal and Polyclonal Antibodies Research
- Hepatitis C virus research
- Hepatocellular Carcinoma Treatment and Prognosis
- Epigenetics and DNA Methylation
- Cell Adhesion Molecules Research
- Click Chemistry and Applications
- Cytokine Signaling Pathways and Interactions
- HIV/AIDS drug development and treatment
- Systemic Lupus Erythematosus Research
- Genetic and rare skin diseases.
- Cellular Mechanics and Interactions
- Hedgehog Signaling Pathway Studies
- Cell death mechanisms and regulation
- Chemical Synthesis and Analysis
- Microtubule and mitosis dynamics
- Plant Virus Research Studies
- Cancer therapeutics and mechanisms
Blueprint Medicines (United States)
2014-2019
Harvard University
1999-2010
Massachusetts General Hospital
2010
Inserm
2009
Université Claude Bernard Lyon 1
2009
Infinity Pharmaceuticals (United States)
2008-2009
Beth Israel Deaconess Medical Center
1999-2005
Aberrant signaling through the fibroblast growth factor 19 (FGF19)/fibroblast receptor 4 (FGFR 4) complex has been shown to cause hepatocellular carcinoma (HCC) in mice and implicated play a similar role humans. We have developed BLU9931, potent irreversible small-molecule inhibitor of FGFR4, as targeted therapy treat patients with HCC whose tumors an activated FGFR4 pathway. BLU9931 is exquisitely selective for versus other FGFR family members all kinases. shows remarkable antitumor...
Abstract Outcomes for patients with advanced hepatocellular carcinoma (HCC) remain poor despite recent progress in drug development. Emerging data implicate FGF19 as a potential HCC driver, suggesting its receptor, FGFR4, novel therapeutic target. We evaluated fisogatinib (BLU-554), highly potent and selective oral FGFR4 inhibitor, phase I dose-escalation/dose-expansion study using expression measured by IHC biomarker pathway activation. For dose escalation, 25 received 140 to 900 mg once...
The integrin family of cell adhesion receptors are important for a diverse set biological responses during development. Although many integrins have been shown to engage similar cytoplasmic effector proteins in vitro, the importance these events mediated by different and ligands is uncertain. We examined role one best-characterized effectors, focal protein paxillin, disruption paxillin gene mice. Paxillin was found be critically involved regulating development mesodermally derived structures...
Recent evidence suggests that blocking aberrant hedgehog pathway signaling may be a promising therapeutic strategy for the treatment of several types cancer. Cyclopamine, plant Veratrum alkaloid, is natural product antagonist pathway. In previous report, seven-membered D-ring semisynthetic analogue cyclopamine, IPI-269609 (2), was shown to have greater acid stability and better aqueous solubility compared cyclopamine. Further modifications A-ring system generated three series analogues with...
ABSTRACT Paxillin is a focal adhesion scaffolding protein which was originally identified as substrate of the oncogenic tyrosine kinase, v-src. has been proposed to be involved in regulation dynamics. Two alternatively spliced mouse paxillin cDNAs were cloned and process, paxillin-related protein, Hic-5, also identified. Cloning characterization Hic-5 indicates that this shares extensive homology with paxillin. Although characterized TGF-β-inducible gene transcription factor senescence,...
Herein is reported the synthesis of a novel class hedgehog antagonists derived from cyclopamine. The acid sensitive D-ring cyclopamine was homologated utilizing sequence chemoselective cyclopropanation and stereoselective acid-catalyzed rearrangement. Further modification A/B-ring homoallylic alcohol to conjugated ketone led discovery new analogues with improved pharmaceutical properties in vitro potency (EC 50) ranging 10 1000 nM.
Human endogenous retroviruses (HERVs) comprise nearly 8% of the human genome and are derived from ancient integrations into germline. The biology HERVs is poorly defined, but there accumulating evidence supporting pathological roles in diverse diseases, such as cancer, autoimmune, neurodegenerative diseases. Functional proteins produced by HERV-encoded genes, including reverse transcriptases (RTs), which could be a contributor to pathology attributed aberrant HERV-K expression. To facilitate...
Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and a driver for many cancers. NST-628 is potent pan-RAF-MEK molecular glue that prevents phosphorylation activation of MEK by RAF, overcoming limitations traditional inhibitors leading to deep durable inhibition pathway. Cellular, biochemical, structural analyses RAF-MEK complexes show engages all isoforms RAF formation BRAF-CRAF heterodimers, differentiated mechanism from current inhibitors. With...
Paxillin is a prominent focal adhesion docking protein that regulates cell and migration. Although numerous paxillin-binding proteins have been identified paxillin required for normal embryogenesis, the precise mechanism by which functions in vivo has not yet determined. We an ortholog of mammalian Drosophila (Dpax) undertaken genetic analysis function during development. Overexpression Dpax disrupted leg wing development, suggesting role imaginal disc morphogenesis. These defects may...
Recently, the importance of targeted covalent inhibitors in addressing potency, selectivity and drug resistance has become great interest, especially area non-small cell lung cancer (NSCLC). Although several EGFR TKIs that are advancing NSCLC clinical development active against mutations which refractory to reversible TKI drugs Tarceva Iressa, limited chemical diversity been explored; all irreversible compounds share same quinazoline scaffold. We describe design a novel pyrimidine-based...
β-Catenin signaling plays a key role in variety of cellular contexts during embryonic development and tissue differentiation. Aberrant β-catenin has also been implicated promoting human colorectal carcinomas as well other cancers. To study the molecular biological functions controlled fashion, we created regulatable form activated by fusion to modified estrogen receptor (ER) ligand binding domain (G525R). Transfection culture cells with expression vectors encoding this hybrid protein allows...
Abstract Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. Chemotherapy has proven ineffective, and Sorafenib remains only approved targeted drug with no second or line treatment options. slows growth advanced liver cancers helps some patients live longer - by an average about three months. There a pressing need for more effective therapies. FGF19 highly controlled hormone normally expressed in intestine, that acts to regulate bile acid synthesis...
Abstract Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and drivers for many cancers. Apart from approved mutation-selective inhibitors BRAF Class I KRAS G12C mutations, other mutations of RAS RAF not directly addressable by currently there is a need therapeutic strategies having superior efficacy, durability tolerability MAPK pathway. NST-628 potent pan-RAF-MEK molecular glue that prevents phosphorylation activation MEK RAF. In this way, overcomes...
<p>Supplementary methods with detailed protein production, mass spectrometry, in vivo, and vitro methodology</p>
<div>Abstract<p>Alterations in the RAS–MAPK signaling cascade are common across multiple solid tumor types and a driver for many cancers. NST-628 is potent pan-RAF–MEK molecular glue that prevents phosphorylation activation of MEK by RAF, overcoming limitations traditional inhibitors leading to deep durable inhibition pathway. Cellular, biochemical, structural analyses RAF–MEK complexes show engages all isoforms RAF formation BRAF–CRAF heterodimers, differentiated mechanism from...