A5031446167- Cancer Immunotherapy and Biomarkers
- Epigenetics and DNA Methylation
- Advanced Breast Cancer Therapies
- Histone Deacetylase Inhibitors Research
- Fibroblast Growth Factor Research
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Luminescence and Fluorescent Materials
- Molecular Sensors and Ion Detection
- Monoclonal and Polyclonal Antibodies Research
- Acute Myeloid Leukemia Research
- CAR-T cell therapy research
- Porphyrin and Phthalocyanine Chemistry
- Advanced Fluorescence Microscopy Techniques
- Photoreceptor and optogenetics research
- Cancer, Hypoxia, and Metabolism
- Immune cells in cancer
- Click Chemistry and Applications
- Kruppel-like factors research
- Cancer-related gene regulation
- Medical Imaging and Pathology Studies
- Synthesis of β-Lactam Compounds
- Advanced biosensing and bioanalysis techniques
- Photochromic and Fluorescence Chemistry
- PARP inhibition in cancer therapy
Incyte (United States)
2015-2024
Wilmington University
2017
South China University of Technology
2015
Texas A&M University
2008-2014
University of California, Berkeley
2011-2013
Alterations in fibroblast growth factor receptor (FGFR) genes have been identified as potential driver oncogenes. Pharmacological targeting of FGFRs may therefore provide therapeutic benefit to selected cancer patients, and proof-of-concept has established early clinical trials FGFR inhibitors. Here, we present the molecular structure preclinical characterization INCB054828 (pemigatinib), a novel, selective inhibitor 1, 2, 3, currently phase 2 trials. pharmacokinetics pharmacodynamics were...
Blocking the activity of programmed cell death protein 1 (PD-1) inhibitory receptor with therapeutic antibodies against either ligand (PD-L1) or PD-1 itself has proven to be an effective treatment modality for multiple cancers. Contrasting antibodies, small molecules could demonstrate increased tissue penetration, distinct pharmacology, and potentially enhanced antitumor activity. Here, we describe identification characterization INCB086550, a novel, oral, small-molecule PD-L1 inhibitor. In...
Eight B-containing compounds, i.e., 1a-h, were prepared as mimics of the green fluorescent protein (GFP) fluorophore. The underlying concept was that synthetic GFP chromophore analogues are not primarily because free rotation about an aryl-alkene bond (Figure 1b). This is possible in beta-barrel GFP; hence, molecule strongly fluorescent. In compounds radiationless decay via this mechanism prevented by complexation BF2 entity. target materials two methods; most obtained according to novel...
BODIPY dyes were synthesized from pyrrole-2-carbaldehyde derivatives in high yields; this constitutes a new approach to dye framework.
Aberrant activation of FGFR has been linked to the pathogenesis many tumor types. Selective inhibition emerged as a promising approach for cancer treatment. Herein, we describe discovery compound 38 (INCB054828, pemigatinib), highly potent and selective inhibitor FGFR1, FGFR2, FGFR3 with excellent physiochemical properties pharmacokinetic profiles. Pemigatinib received accelerated approval from U.S. Food Drug Administration treatment adults previously treated, unresectable locally advanced...
CDK2 is a critical regulator of the cell cycle. For variety human cancers, dysregulation CDK2/cyclin E1 can lead to tumor growth and proliferation. Historically, early efforts develop inhibitors with clinical applications proved unsuccessful due challenges in achieving selectivity over off-target CDK isoforms associated toxicity. In this report, we describe discovery (4-pyrazolyl)-2-aminopyrimidines as potent class that display CDKs 1, 4, 6, 7, 9. SAR studies led identification compound 17,...
There is a close structural similarity between rosamines A and rhodamines B, yet diversity of structures in the rosamine class their spectral properties have to be explored depth. This manuscript describes concise, scalable, solution-phase method obtain 1−5 12−15, which include some water-soluble derivatives. In one test case (for 15) an illustrative protein conjugate was also formed. Throughout these products were isolated purified, syntheses found scalable. Further, with cyclic amine...
Abstract Tumors with defects in mismatch repair genes can present microsatellite instability (MSI) characterized by expansions of short, repeated DNA sequences. Functional genomic screens revealed that MSI-high (MSI-H) cell lines were uniquely vulnerable to depletion Werner (WRN) which encodes an ATP-dependent helicase. Importantly inhibitors WRN phenocopy genetic leading selective inhibition MSI-H tumor growth. SNV5686 is a novel, reversible inhibitor potent inhibitory activity biochemical...
SNV1521 is clinical stage PARP1 inhibitor and trapper with excellent potency selectivity against other MARP PARP proteins. Although several first generation non-PARP1 selective inhibitors have been approved primarily as monotherapy for BRCA-associated tumors, they not fully realized the potential of inhibition a mechanism potentiation chemo-, DNA damage response, radiation therapy because overlapping toxicities including hematologic suppression. shows exquisite over PARP2 related proteins in...
ADVERTISEMENT RETURN TO ISSUEPREVLetterNEXTFluorescent Amino- and Thiopyronin DyesLiangxing Wu Kevin BurgessView Author Information Texas A & M University, Chemistry Department, P.O. Box 30012, College Station, 77842[email protected]Cite this: Org. Lett. 2008, 10, 9, 1779–1782Publication Date (Web):April 2008Publication History Received7 March 2008Published online9 April inissue 1 May 2008https://pubs.acs.org/doi/10.1021/ol800526shttps://doi.org/10.1021/ol800526srapid-communicationACS...
Two water-soluble "through-bond energy transfer cassettes" (TBET-cassettes) were prepared. They have good extinction coefficients at the donor part and to acceptor parts with "overall quantum yields" (0.30 0.24 in pH 7.4 phosphate buffer). Fluorescence resonance from one protein functionalized an appropriate can be used excite TBET-cassettes on different proteins probe protein−protein interactions under conditions that would not possible for single-dye systems.
Abstract Acute myeloid leukemia (AML) is a disease characterized by the expansion of hematopoietic stem cell like population caused in part block differentiation. In AML, an altered epigenetic landscape, often arising from genetic lesions regulators, enforces oncogenic expression profile and suppresses Lysine specific demethylase 1 (LSD1) catalyzes demethylation lysine 4 9 histone H3 through FAD-dependent redox process. Aberrant LSD1 activity has been proposed to maintain programs prevent...
An optically controlled Ca2+-chelator 1 was developed to mimic natural calcium oscillations. Compound 1, a spiroamido-rhodamine derivative of 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA), underwent cycles reversible transitions between colorless closed state and fluorescent open form. The closed-state exhibited high affinity for Ca2+ (Kd: 509 nM) with excellent selectivity over Mg2+ 19 mM). isomer had 350-fold lower 181 μM), while the not significantly affected 14
Abstract Methylated histone marks on H3K4 and H3K9 are generally coupled with transcriptional activation repression, respectively. Altered levels of these methylation lead to abnormal gene expression associated oncogenesis. Lysine specific demethylase 1 (LSD1) catalyzes demethylation mono di-methylated lysine 4 9 H3 via an FAD-dependent redox-process. Deregulated LSD1 activity perturbs normal can cellular transformation. In particular, the function has been reported maintain stem cell-like...
Herein, for the first time, outstanding laser performance is demonstrated in liquid solution and solid state by naturally assembling excimers of organic fluorophores (rosamine dyes). Highly efficient photostable dye properties, with broadened tunability covering 80 nm red spectral region (590–670 nm), attributed to coexistence monomers induced under high optical gain conditions. Amplified spontaneous emission measurements rosamine‐doped polymer thin films show that excimer exhibits a...
A series of exceptionally selective CDK2 inhibitors are described. Starting from an HTS hit, we successfully scaffold hopped to a 5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one core structure, which imparted promising initial selectivity within the CDK family. Extensive further SAR identified additional factors that drove above 200× for CDKs 1/4/6/7/9. General kinome was also greatly improved. Finally, use in vivo metabolite identification allowed us pinpoint sulfonamide dealkylation as...
Reprogramming of energy metabolism is pivotal to cancer, so mitochondria are potential targets for anticancer therapy. A prior study has demonstrated the anti-proliferative activity a new class mitochondria-targeting rosamines. This present describes in vitro cytotoxicity second-generation rosamine analogs, their mode action, and vivo efficacies tumor allografted mouse model. Here, we showed that these compounds exhibited potent (average IC50<0.5 µM), inhibited Complex II ATP synthase...
Activin receptor-like kinase 2 (ALK2) is a transmembrane receptor that mediates the signaling of members TGF-β superfamily. The aberrant activation ALK2 has been linked to rare genetic disorder fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) are associated with severely reduced life expectancy in pediatric patients. also shown play an essential role iron metabolism by regulating hepcidin levels affecting anemia chronic disease. Thus, selective...
Abstract Aberrant signaling through Fibroblast Growth Factor Receptors (FGFR) has been reported in multiple types of human cancers. Genomic analyses squamous cell lung, gastric and urothelial tumors have revealed recurrent genetic alterations FGFR1, FGFR2 FGFR3 genes, respectively. FGFR proteins contribute to the development malignancies by promoting tumor proliferation, survival, migration supporting angiogenesis. Therefore targeting kinases may provide therapeutic benefit patients with...
Conventional cytotoxic anticancer drugs that target all rapidly dividing cells are nonselective in their mechanism of action, because they disrupt essential components crucial to both malignant and proliferating normal cells. Instead, targeting cellular functions distinctly different between cancer may provide a basis for selective killing tumor One such strategy is still largely unexplored utilize the relatively higher negative mitochondrial membrane potential carcinoma compared with...
We present the design, synthesis and characterization of new functionalized fluorescent optical switches for rapid, all-visible light-mediated manipulation fluorescence signals from labelled structures within living cells, as probes high-contrast lock-in detection (OLID) imaging microscopy. A triazole-substituted BIPS (TzBIPS) is identified a rational synthetic design strategy that undergoes robust, rapid reversible, visible light-driven transitions between colorless spiro- (SP) far-red...