A5046896380- Protein Tyrosine Phosphatases
- Melanoma and MAPK Pathways
- Galectins and Cancer Biology
- Synthesis and biological activity
- PI3K/AKT/mTOR signaling in cancer
- Hippo pathway signaling and YAP/TAZ
- Glycosylation and Glycoproteins Research
- Lung Cancer Treatments and Mutations
- Protein Kinase Regulation and GTPase Signaling
- interferon and immune responses
- Colorectal Cancer Treatments and Studies
- Ubiquitin and proteasome pathways
- Biochemical and Molecular Research
- Immune cells in cancer
- Bioactive Compounds and Antitumor Agents
- Cytokine Signaling Pathways and Interactions
- RNA modifications and cancer
- ATP Synthase and ATPases Research
- Ferroptosis and cancer prognosis
- RNA Research and Splicing
- Cancer Research and Treatments
- Pancreatic and Hepatic Oncology Research
- Atherosclerosis and Cardiovascular Diseases
- Fibroblast Growth Factor Research
- Chemokine receptors and signaling
Shahid Beheshti University of Medical Sciences
2024-2025
Bristol-Myers Squibb (United States)
2024
Novartis Institutes for BioMedical Research
2021
Novartis (United States)
2018-2021
Novartis (Switzerland)
2021
Foundation for Biomedical Research
2020
AstraZeneca (United States)
2015-2016
Boston Children's Hospital
2011-2014
Harvard University
2006-2014
Harvard Stem Cell Institute
2011-2014
Systemically administered antisense oligonucleotide AZD9150 inhibits STAT3 and shows anticancer activity in preclinical models patients.
SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene and involved in cell growth differentiation via MAPK signaling pathway. also plays an important role programed death pathway (PD-1/PD-L1). As oncoprotein as well potential immunomodulator, controlling activity of high therapeutic interest. part our comprehensive program targeting SHP2, we identified multiple allosteric binding modes inhibition optimized numerous chemical scaffolds parallel. In this drug annotation...
Activating mutations in PTPN11, encoding the cytosolic protein tyrosine phosphatase SHP2, result developmental disorders and act as oncogenic drivers patients with hematologic cancers. The allosteric inhibitor SHP099 stabilizes wild-type SHP2 enzyme an autoinhibited conformation that is itself destabilized by mutations. Here, we report impact of highly activated most frequently observed mutation, E76K, on structure investigate effect E76K other inhibition SHP099. SHP2E76K adopts open but can...
Abstract Purpose: SHP2 inhibitors offer an appealing and novel approach to inhibit receptor tyrosine kinase (RTK) signaling, which is the oncogenic driver in many tumors or frequently feedback activated response targeted therapies including RTK MAPK inhibitors. We seek evaluate efficacy synergistic mechanisms of combinations with a inhibitor, TNO155, inform their clinical development. Experimental Design: The TNO155 EGFR (EGFRi), BRAFi, KRASG12Ci, CDK4/6i, anti–programmed cell death-1 (PD-1)...
Protein tyrosine phosphatase SHP2 is an oncoprotein associated with cancer as well a potential immune modulator because of its role in the programmed cell death PD-L1/PD-1 pathway. In preceding manuscript, we described optimization fused, bicyclic screening hit for potency, selectivity, and physicochemical properties order to further expand chemical diversity allosteric inhibitors. this describe expansion our approach, morphing system into novel monocyclic pyrimidinone scaffold through...
FGFR1 was recently shown to be activated as part of a compensatory response prolonged treatment with the MEK inhibitor trametinib in several KRAS-mutant lung and pancreatic cancer cell lines. We hypothesize that other receptor tyrosine kinases (RTK) are also feedback-activated this context. Herein, we profile large panel lines for contribution RTKs feedback activation phospho-MEK following inhibition, using an SHP2 (SHP099) blocks RAS mediated by multiple RTKs. find RTK-driven widely exists...
SHP2 is a nonreceptor protein tyrosine phosphatase within the mitogen-activated kinase (MAPK) pathway controlling cell growth, differentiation, and oncogenic transformation. also participates in programed death (PD-1/PD-L1) governing immune surveillance. Small-molecule inhibition of has been widely investigated, including our previous reports describing SHP099 (2), which binds to tunnel-like allosteric binding site. To broaden approach SHP2, we conducted additional hit finding, evaluation,...
Abstract SHP2 is a ubiquitous tyrosine phosphatase involved in regulating both tumor and immune cell signaling. In this study, we discovered novel modulatory function of SHP2. Targeting protein with allosteric inhibitors promoted anti-tumor immunity, including enhancing T cytotoxic immune-mediated regression. Knockout using CRISPR/Cas9 gene editing showed that targeting cancer cells contributes to response. Inhibition activity augmented intrinsic IFNγ signaling resulting enhanced...
Cell density, the ratio of cell mass to volume, is an indicator molecular crowding and therefore a fundamental determinant state function. However, existing density measurements lack precision or throughput quantify subtle differences in states, particularly primary samples. Here we present approach for measuring 30,000 single cells per hour with 0.03% (0.0003 g/mL) by integrating fluorescence exclusion microscopy suspended microchannel resonator. Applying this human lymphocytes, discovered...
Dematin and adducin are actin-binding proteins located at the spectrin-actin junctions, also called junctional complex, in erythrocyte membrane. Here we propose a new model whereby dematin link complex to human plasma Using combination of surface labeling, immunoprecipitation, vesicle proteomics approaches, have identified glucose transporter-1 as receptor for This finding is first description transmembrane protein that binds adducin, thus providing rationale attachment lipid bilayer....
KRAS, an oncogene mutated in nearly one third of human cancers, remains a pharmacologic challenge for direct inhibition except recent advances selective inhibitors targeting the G12C variant. Here, we report that protein tyrosine phosphatase, SHP2, can impair proliferation KRAS-mutant cancer cells vitro and vivo using cell line xenografts primary tumors. In vitro, sensitivity toward allosteric SHP2 inhibitor, SHP099, is not apparent when are grown on plastic 2D monolayer, but revealed as 3D...
// Hengyu Lu 1 , Chen Liu Hung Huynh 2 Thi Bich Uyen Le Matthew J. LaMarche 3 Morvarid Mohseni Jeffrey A. Engelman Peter S. Hammerman Giordano Caponigro and Huai-Xiang Hao Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, Massachusetts, USA Laboratory of Molecular Endocrinology, Division Cellular National Cancer Centre, Singapore Global Discovery Chemistry, Correspondence to: Hao, email: huaixiang.hao@novartis.com Keywords: SHP2; FGFR; resistance; feedback...
SHP2 is a protein tyrosine phosphatase that normally potentiates intracellular signaling by growth factors, antigen receptors, and some cytokines, yet frequently mutated in human cancer. Here, we examine the role of responses breast cancer cells to EGF monitoring phosphoproteome dynamics when allosterically inhibited SHP099. The phosphotyrosine abundance at more than 400 residues reveal six distinct response signatures following SHP099 treatment washout. Remarkably, addition newly identified...
Endometriosis is a chronic inflammatory disease characterized by the presence of endometrial lesions outside uterus. Current treatment methods primarily focus on hormone-based therapy or invasive procedures. However, given crucial role immune system in initiation and progression, there an opportunity to explore new approaches. Bispecific antibodies, which bind two different cells using their bivalent arms, have shown promise treating cancers autoimmune diseases. This study postulates that,...
Antibody-drug conjugates (ADCs) are a novel modality that allows targeted delivery of potent therapeutic agents to the desired site. Herein we report our discovery NAMPT inhibitors as nonantimitotic payload for ADCs. The resulting anti-c-Kit (ADC-3 and ADC-4) demonstrated in vivo efficacy c-Kit positive gastrointestinal stromal tumor GIST-T1 xenograft model target-dependent manner.
In patients with acute myeloid leukemia (AML), 10% to 30% the normal karyotype express mutations in regulators of DNA methylation, such as TET2 or DNMT3A, conjunction activating mutation receptor tyrosine kinase FLT3. These have a poor prognosis because they do not respond well established therapies. Here, utilizing mouse models AML that recapitulate cardinal features human disease and bear combination loss-of-function either Tet2 Dnmt3a along expression Flt3ITD, we show inhibition protein...
// Brendon Ladd 1 , Anne Marie Mazzola Teeru Bihani Zhongwu Lai James Bradford 2 Michael Collins Evan Barry U. Goeppert Hazel M. Weir Kelly Hearne Jonathan G. Renshaw Morvarid Mohseni Elaine Hurt 3 Sanjoo Jalla Haifeng Bao Robert Hollingsworth Corinne Reimer Zinda Stephen Fawell and Celina D'Cruz Oncology iMed, AstraZeneca, Gatehouse Park, Waltham, MA, USA Alderley Macclesfield, UK Oncology, Medimmune, Gaithersburg, MD, Correspondence to: D'Cruz, email: Keywords : advanced metastatic breast...