A5103178677- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Hydrology and Drought Analysis
- Hydrology and Watershed Management Studies
- Metal-Catalyzed Oxygenation Mechanisms
- Estrogen and related hormone effects
- Histone Deacetylase Inhibitors Research
- Phenothiazines and Benzothiazines Synthesis and Activities
- Flood Risk Assessment and Management
- Cancer-related Molecular Pathways
- Peptidase Inhibition and Analysis
- Climate variability and models
- Metal complexes synthesis and properties
- PI3K/AKT/mTOR signaling in cancer
- Cancer Mechanisms and Therapy
- HER2/EGFR in Cancer Research
- Quinazolinone synthesis and applications
- Crystallography and molecular interactions
- Protein Kinase Regulation and GTPase Signaling
- Synthesis and Biological Evaluation
- Porphyrin and Phthalocyanine Chemistry
- Synthesis and Characterization of Heterocyclic Compounds
- Computational Drug Discovery Methods
- Angiogenesis and VEGF in Cancer
- Protein Degradation and Inhibitors
Central University of Himachal Pradesh
2025
Indian Institute of Technology Kanpur
2022-2025
All India Institute of Medical Sciences
2012-2024
Sharda University
2022-2024
Virginia Commonwealth University
2019-2023
Rutgers, The State University of New Jersey
2019-2023
Rutgers New Jersey Medical School
2019-2023
Institute of Microbial Technology
2023
Swami Rama Himalayan University
2021-2023
Institute of Medical Sciences
2022-2023
Protein kinase R (PKR)-like endoplasmic reticulum (PERK) is activated in response to a variety of stresses implicated numerous disease states. Evidence that PERK tumorigenesis and cancer cell survival stimulated our search for small molecule inhibitors. Through screening lead optimization using the human crystal structure, we discovered compound 38 (GSK2606414), an orally available, potent, selective inhibitor. Compound inhibits activation cells growth tumor xenograft mice.
Inhibition of the vascular endothelial growth factor (VEGF) signaling pathway has emerged as one most promising new approaches for cancer therapy. We describe herein key steps starting from an initial screening hit leading to discovery pazopanib, N4-(2,3-dimethyl-2H-indazol-6-yl)-N4-methyl-N2-(4-methyl-3-sulfonamidophenyl)-2,4-pyrimidinediamine, a potent pan-VEGF receptor (VEGFR) inhibitor under clinical development renal-cell and other solid tumors.
Akt kinases 1, 2, and 3 are important regulators of cell survival have been shown to be constitutively active in a variety human tumors. GSK690693 is novel ATP-competitive, low-nanomolar pan-Akt kinase inhibitor. It selective for the isoforms versus majority other families; however, it does inhibit additional members AGC family. causes dose-dependent reductions phosphorylation state multiple proteins downstream Akt, including GSK3 beta, PRAS40, Forkhead. inhibited proliferation induced...
We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor protein kinase R (PKR)-like endoplasmic reticulum (PERK), which inhibited PERK activation cells and demonstrated tumor growth inhibition human xenograft mice. In continuation our drug program, we applied strategy to decrease lipophilicity as means improve physical properties pharmacokinetics. This report describes medicinal chemistry optimization culminating GSK2656157 (6), was selected for advancement...
Oncogenic BRAF alleles are both necessary and sufficient for cellular transformation, suggesting that chemical inhibition of the activated mutant protein kinase may reverse tumor phenotype. Here, we report characterization SB-590885, a novel triarylimidazole selectively inhibits Raf kinases with more potency towards B-Raf than c-Raf. Crystallographic analysis revealed SB-590885 stabilizes oncogenic domain in an active configuration, which is distinct from previously reported mechanism action...
A critical role for vascular endothelial factor (VEGF) has been demonstrated in multiple myeloma (MM) pathogenesis. Here, we characterized the effect of small-molecule VEGF receptor inhibitor pazopanib on MM cells bone marrow milieu. Pazopanib inhibits VEGF-triggered signaling pathways both tumor and cells, thereby blocking vitro cell growth, survival, migration, VEGF-induced up-regulation adhesion molecules abrogating cell-MM binding associated proliferation. We show that is first-in-class...
p21-activated kinase 1 (Pak1) has been shown recently to induce hyperplasia in the mammary epithelium, a phenotype also manifested by overexpression of cyclin D1, known indicator proliferative stage. Here we investigated role Pak1 pathway expression D1 using tissue culture models and transgenic mice expressing activated glands. We found that hyperplastic glands from catalytically active exhibit 5- 7-fold increased as compared with stage-matched wild-type mice. In addition, levels were...
p21-activated kinase 1 (Pak1) phosphorylates many proteins in both normal and transformed cells. Its ability to phosphorylate thereby activate the estrogen receptor alpha (ERalpha) potentially limits effectiveness of antiestrogen treatment breast cancer. Here we studied associations between Pak1 expression subcellular localization tumor cells tamoxifen resistance.Pak1 protein was evaluated 403 primary tumors from premenopausal patients who had been randomly assigned 2 years adjuvant or no...
The actin cross-linking protein filamin A (FLNa) functions as a scaffolding and couples cell cytoskeleton to extracellular matrix integrin receptor signaling. In this study, we report that FLNa suppresses invasion of breast cancer cells regulates focal adhesion (FA) turnover. Two large progression tissue microarrays from patients revealed significant decrease levels in tissues invasive compared with benign disease lymph node-positive node-negative cancer. orthotopic mouse models,...
Tumor cells upregulate many cell signaling pathways, with AKT being one of the key kinases to be activated in a variety malignancies. GSK2110183 and GSK2141795 are orally bioavailable, potent inhibitors that have progressed human clinical studies. Both compounds selective, ATP-competitive 1, 2 3. Cells treated either compound show decreased phosphorylation several substrates downstream AKT. desirable pharmaceutical properties daily oral dosing results sustained inhibition activity as well...
Stimulation of growth factor signaling has been implicated in the development invasive phenotype and p21-activated kinase (PAK1) activation human breast epithelial cancer cells. To further explore roles PAK1 behavior cells, present study we investigated influence inhibition activity on reorganization cytoskeleton components that control motility invasiveness using a highly MDA-MB435 as model system. Our results demonstrate overexpression dead K299R mutant leads to suppression motile...
Abstract Purpose: Insulin-like growth factor type I receptor (IGF-IR) plays critical roles in epithelial cancer cell development, proliferation, motility, and survival, new therapeutic agents targeting IGF-IR are development. Another tyrosine kinase, the epidermal (EGFR), is an established target head neck IGF-IR/EGFR heterodimerization has been reported other cancers. The present study was undertaken to determine effects of anti–IGF-IR on signaling phenotypes squamous carcinomas (SCCHN)....
Globally, gastric cancer is the second most common cause of cancer-related death, with majority health burden borne by economically less-developed countries.Here, we report a genetic characterization 50 adenocarcinoma samples, using affymetrix SNP arrays and Illumina mRNA expression as well sequencing coding regions 384 genes belonging to various pathways known be altered in other cancers.Genetic alterations were observed WNT, Hedgehog, cell cycle, DNA damage...
The emergence of multidrug resistance in cancer cells necessitates the development new therapeutic modalities. One way orchestrate energy metabolism and redox homeostasis is through overloaded iron pools directed by regulatory proteins, including transferrin. Here, we demonstrate that targeting using nitrogen-based heterocyclic chelators their complexes efficiently prevents proliferation liver (EC
Data of 13 stream flow gauging sites the North Brahmaputra region India are screened using discordancy measure (Di) and homogeneity is then tested employing L-moments based heterogeneity (H). For computing H, 500 simulations performed Kappa distribution. Based on this test, it observed that data 10 out constitute a homogeneous region. Comparative regional flood frequency analysis studies conducted commonly used distributions. L-moment ratio diagram ∣Zidist∣-statistic criteria, general...
Abstract Purpose: Chromatin remodeling pathways are critical in the regulation of cancer-related genes and currently being explored as potential targets for therapeutic intervention. The metastasis tumor antigen (MTA) family proteins, MTA1, MTA2, MTA3, components chromatin with roles breast cancer. Although all three MTA proteins have been shown to be associated metastatic progression cancers, expression characteristic MTA1-3 a multistep cancer model remains unknown. Structural functional...
Abstract As a tumor marker for colorectal cancers, carcinoembryonic antigen (CEA) enhances the metastatic potential of cancer cells. CEA functions as an intercellular adhesion molecule and is upregulated in wide variety human cancers. However, molecular mechanisms by which mediates metastasis remain to be understood. Transforming growth factor-β (TGF-β) signaling regulates both suppression metastasis, also contributes stimulation transcription secretion it remains unknown whether CEA, turn,...
Anaplastic thyroid cancer (ATC) has perhaps the worst prognosis of any cancer, with a median survival only about 5 months regardless stage. Pazopanib monotherapy promising clinical activity in differentiated cancers (generally attributed to vascular endothelial growth factor receptor inhibition), yet less effective single-agent ATC. We now report that combining pazopanib microtubule inhibitors such as paclitaxel produced heightened and synergistic antitumor effects ATC cells xenografts were...