A5024438197- Protein Degradation and Inhibitors
- Cancer-related Molecular Pathways
- Advanced Breast Cancer Therapies
- Fibroblast Growth Factor Research
- Cancer Mechanisms and Therapy
- Ubiquitin and proteasome pathways
- Click Chemistry and Applications
- Histone Deacetylase Inhibitors Research
- Cancer therapeutics and mechanisms
- Chromatin Remodeling and Cancer
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Synthesis and biological activity
- Computational Drug Discovery Methods
- Peptidase Inhibition and Analysis
- PARP inhibition in cancer therapy
- Epigenetics and DNA Methylation
- Sirtuins and Resveratrol in Medicine
- Hippo pathway signaling and YAP/TAZ
- Diabetes Treatment and Management
- Cancer-related gene regulation
- RNA modifications and cancer
- Biochemical and Molecular Research
- Kruppel-like factors research
- Cytokine Signaling Pathways and Interactions
Aurigene Discovery Technologies (India)
2012-2022
Stimulation of the G protein coupled receptor GPR120 has been shown to have anti-inflammatory and insulin-sensitizing effects, promote glucagon like peptide-1 (GLP-1) secretion, play a key role in sensing dietary fat control energy balance. In search for differentially expressed genes potentially involved food intake body-weight regulation we identified be regulated intestine selectively bred diet induced obese (DIO) resistant (DR) rats. Subsequently investigated effect stimulation with long...
Small molecule potent IRAK4 inhibitors from a novel bicyclic heterocycle class were designed and synthesized based on hits identified Aurigene's compound library. The advanced lead compound, CA-4948, demonstrated good cellular activity in ABC DLBCL AML cell lines. Inhibition of TLR signaling leading to decreased IL-6 levels was also observed whole blood assays. CA-4948 moderate high selectivity panel 329 kinases as well exhibited desirable ADME PK profiles including oral bioavailability...
Alterations in the gene encoding for FGFR and upregulation of VEGFR are found often cancer, which correlate with disease progression unfavorable survival. In addition, signaling synergistically promote tumor angiogenesis, activation has been described as functional compensatory angiogenic signal following development resistance to inhibition. Several selective small-molecule kinase inhibitors currently clinical development. ODM-203 is a novel, selective, equipotent inhibitor families. this...
We describe the synthesis and characterization of 3-alkoxy-pyrrolo[1,2-b]pyrazolines as novel selective androgen receptor (AR) modulators that possess excellent physicochemical properties for transdermal administration. Compound 26 bound to human AR with an IC50 0.7 nM great selectivity over other nuclear hormone receptors potently activated in a C2C12 muscle cell reporter gene assay EC50 0.5 nM. It showed high aqueous solubility 1.3 g/L at pH 7.4, silico model well customized parallel...
Abstract The prevalence of obesity is increasing with an alarming rate worldwide and there a need for efficacious satiety drugs. PYY3–36 has been shown to play role in hypothalamic appetite regulation novel analogs targeting the Y2 receptor have potential as drugs treatment obesity. We designed series isoforms, by first adding dipeptide Ile–Lys N ‐terminal α Ser‐13 PYY13–36 then anchoring segment, e.g. PYY3–12, new Lys ε ‐amine. hypothesized that such modifications would alter folding PYY,...
Mutations in MEK1/2 have been described as a resistance mechanism to BRAF/MEK inhibitor treatment. We report the discovery of novel ATP-competitive with efficacy wildtype (WT) and mutant MEK12 models. Starting from HTS hit, we obtained selective, cellularly active compounds that showed equipotent inhibition WT panel cell lines. Using structure-based approach, optimization addressed liabilities by systematic analysis molecular matched pairs (MMPs) ligand conformation. Addition only three...
Abstract Regulatory T cells (Tregs), an immunosuppressive subset of CD4+ cells, play a vital role in maintaining immune homeostasis by regulating response to self antigens and tolerance. On the contrary, Tregs infiltrating tumor microenvironment (TME) impede effective anti-tumor immunity inhibiting tumor-specific cell responses generating suppressive TME, thus promoting progression. Clinically, have been proven significant resistance checkpoint inhibitors (ICIs) leading lower rates. Hence,...
Abstract EP300 (or p300) acts as histone acetyltransferase (HAT) and transcriptional adapter or co-activator regulating transcription via chromatin remodeling. Both non-histone proteins are acetylated by p300. In addition to HAT function, p300 has crotonyl-transferase activities, that p300-catalyzed crotonylation directly stimulates a greater degree. functions scaffolding enhancer of different factors like HIF1a, BRCA-1, p53, NFκB, c-Myc, estrogen receptor (ER) androgen (AR) other such PD-L1...
Abstract CBP and p300 are closely related epigenetic modulators that participate in chromatin remodeling transcription play an oncogenic role a variety of cancers. Studies have indicated the selective targeting is highly attractive therapeutic strategy for cancers with mutations because synthetic lethality, those dependent on Wnt/β-catenin signaling ERα HER2-positive breast Prevalence high mutation frequency several including skin (27%), small cell lung (8%), lymphoma (8-13%) bladder cancer...
Abstract Pancreatic cancer is reported to be dependent on NAD salvage pathway for its growth and survival. Nicotinamide phosphoribosyl transferase (NAMPT), an enzyme that catalyzes the rate limiting step of biosynthesis over expressed in a number cancers. Inhibition NAMPT with first generation inhibitors has been demonstrated result anti-tumor efficacy preclinical models. Clinical development hindered because their poor pharmacological profile, high cytochrome inhibition possibly...
Abstract Background: Phosphorylation of the RNA polymerase II (RNAPII) in C-terminal domain (CTD) by Cyclin-dependent kinase 7 (CDK7) is an important step cellular transcription process. Hence pharmacological modulation CDK7 activity considered as interesting approach to treat cancers that critically dependent on maintain their oncogenic state. Experimental procedures: Multiple series novel covalent inhibitors were identified SBDD based binding mode known find early hits. Iterative medicinal...
Abstract Background: The Bromodomain (BRD) and Extra-Terminal domain (BET) family of proteins are key regulators epigenetic control. Although pan BET Inhibitors show good clinical activity, progressive disease was seen after several months treatment in responders, likely due to secondary resistance mechanisms. plausible mechanisms increased expression TCF7L2, c-Myc, Survivin PIM1. Cyclic AMP response element binding protein (CREB)-binding (CBP) E1A interacting 300 kDa (EP300 or p300) two...
Abstract Interleukin-1 Receptor Associated Kinase-4 (IRAK-4) is a serine/threonine protein kinase belonging to tyrosine like (TLK) family. IRAK-4 one of the important signalling components downstream IL-1/Toll family receptors (IL-1R, IL-18R, IL-33R, Toll-like receptors). Recent studies have reported occurrence oncogenic mutations in MYD88 30% ABC diffuse large B cell lymphomas (ABC DLBCL) and 90% Waldenstrom's macroglobulinemia (WM). Most DLBCLs single amino acid substitution proline for...
Abstract Cyclin-dependent kinase 7 (CDK7) is an important constituent of the cellular transcriptional machinery, where it phosphorylates C-terminal domain (CTD) RNAP polymerase II (RNAPII). Because many tumor types are critically dependent on transcription for maintenance their oncogenic state, pharmacological modulation CDK7 activity considered as approach to treat cancer. Multiple series inhibitors were identified by iterative medicinal chemistry efforts and SAR based approach. Early...
Abstract Interleukin-1 receptor associated kinases (IRAKs) are serine/threonine protein belonging to the tyrosine-like kinase (TLK) family. IRAKs function as mediators of Toll-like (TLR) and interleukin-1 (IL-1R) signaling pathways play an important role in innate immune signaling. TLR/IL-1R stimulation leads recruitment MYD88, adaptor molecule, activated complex, which then complexes with IRAK4 activates IRAK1. TRAF6 is by IRAK1 leading NFkB activation. Recent studies have reported...
Abstract Background: Cyclin-dependent kinase 12 (CDK12) coordinately regulates the transcription, splicing, and alternative splicing of several large pre-mRNAs. Defective CDK12 activity has been associated with genomic instability downregulation genes in DNA damage response (DDR) pathway. In addition, depletion impairs alternate a process being increasingly implicated cancer progression. Associated Cyclin K (CycK), transcription elongation by phosphorylating RNA polymerase II (RNAP II) at S2...
Abstract PRMT5 is a typical type II methyltransferase, transferring two methyl groups to arginine, leading symmetric dimethylation of the substrate. It can symmetrically methylate histones H2AR3, H3R2, H3R8, and H4R3 also many non-histone proteins contributing tumorigenesis by regulating cell cycle progression, DNA repair, growth, apoptosis, inflammation. Overexpression reported in several human malignancies including lymphoma, glioma, melanoma, lung, breast, ovarian, prostate cancers....
Abstract Background: SMARCA2 (BRM) and SMARCA4 (BRG1) are two mutually exclusive DNA-dependent ATPases of the SWI/SNF complex, which function in mobilizing nucleosomes to regulate transcription, DNA replication/repair chromosome dynamics. is known be mutated number cancers lacking targetable oncogenes, with SMARCA4-mutant patient population representing 10%-20% NSCLC, 100% small cell ovarian cancer (hypercalcemic type), 28% skin cancer, 16% glioma 14% colon cancer. Genetic studies have...
Abstract Genomic alterations in fibroblast growth factor receptors (FGFR) and upregulation of vascular endothelial (VEGFR) are often found the same cancer types such as gastric, lung breast these correlate with patient survival disease progression. In addition, both FGFR VEGFR signaling promote tumor angiogenesis. Activation has also been described to function a compensatory angiogenic signal following development resistance VEGF inhibition. ODM-203 is novel selective inhibitor families...
Abstract Interleukin-1 receptor associated kinases (IRAKs) are serine/threonine protein belonging to tyrosine-like kinase (TLK) family. The IRAK family consists of IRAK1, IRAK2, IRAK3 and IRAK4 out which only IRAK1 exhibit activity. IRAKs function as mediators Toll-like (TLR) interleukin-1 (IL-1R) signaling pathways play an important role in innate immune signaling. Recent studies have reported the occurrence oncogenic mutations MYD88 30% activated B cell diffuse large B-cell lymphoma (ABC...
Abstract Nicotinamide phosphoribosyl transferase (NAMPT) is the enzyme that catalyzes rate-limiting step in salvage pathway of Adenine Dinucleotide (NAD) biosynthesis. NAMPT overexpressed a number cancers, and inhibition has been shown to result anti-tumor efficacy preclinical models. Clinical development first generation inhibitors hindered because their poor pharmacological profile, high cytochrome possibly mechanism-based toxicities. Therefore, we sought develop with “best-in-class”...
Abstract The nuclear hormone receptor RORγ controls the differentiation of Th17 cells that plays a key pro-inflammatory role in variety autoimmune diseases. inverse agonists from multiple structural classes were discovered and screened radio-ligand binding assay as well cell based reporter functional effect was evaluated using primary mouse/human CD4+ve T-cells to cells. Pharmacokinetic profile potent compounds determined support evaluation efficacy safety rodents. Lead have demonstrated...