Design and Discovery of a Potent and Selective Inhibitor of Integrin αvβ1.

Selective inhibition of the RGD (Arg-Gly-Asp) integrin αvβ1 has been recently identified as an attractive therapeutic approach for the treatment of liver fibrosis given its function, target expression, and safety profile. Our identification of a non-RGD small molecule lead followed by focused, systematic changes to the core structure utilizing a crystal structure, modeling, and a tractable synthetic approach resulted in the identification of a potent small molecule exhibiting a remarkable affinity for αvβ1 relative to several other integrin isoforms measured. Azabenzimidazolone demonstrated antifibrotic efficacy in an rat liver fibrosis model and represents a tool compound capable of further exploring the biological consequences of selective αvβ1 inhibition.

Age- And Gender-Based Predisposition Of MMP-9 -1562 C > T Genotype And Allele Frequencies With Serum MMP-9 Levels As Probable Risk Factors In Patients With Coronary Artery Disease.

Unlabelled: Coronary artery disease (CAD) is the third foremost reason of death worldwide in both men and women of different age groups, and is associated with 17.8 million mortalities annually due to unknown specific genetic background. Hence, we elucidated the age- and gender-based predisposition of MMP-9 -1562 C > T (rs3918242) genotype and allele frequencies along with serum MMP-9 levels as probable risk factors in the development of CAD.

Discovery of the Bruton's Tyrosine Kinase Inhibitor Clinical Candidate TAK-020 ()-5-(1-((1-Acryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-2,4-dihydro-3-1,2,4-triazol-3-one, by Fragment-Based Drug Design.

This publication details the successful use of FBDD (fragment-based drug discovery) principles in the invention of a novel covalent Bruton's tyrosine kinase inhibitor, which ultimately became the Takeda Pharmaceuticals clinical candidate TAK-020. Described herein are the discovery of the fragment 5-phenyl-2,4-dihydro-3-1,2,4-triazol-3-one, the subsequent optimization of this hit molecule to the candidate, and synthesis and performance in pharmacodynamic and efficacy models along with direct biophysical comparison of TAK-020 with other clinical-level assets and the marketed drug Ibrutinib.

Using Target Engagement Biomarkers to Predict Clinical Efficacy of MetAP2 Inhibitors.

Target-engagement pharmacodynamic (PD) biomarkers are valuable tools in the prioritization of drug candidates, especially for novel, first-in-class mechanisms whose robustness to alter disease outcome is unknown. Methionine aminopeptidase 2 (MetAP2) is a cytosolic metalloenzyme that cleaves the N-terminal methionine from nascent proteins. Inhibition of MetAP2 leads to weight loss in obese rodents, dogs and humans.

Identification of differentially expressed transcripts at critical developmental stages in sorghum [ (L.) Moench] in relation to grain yield heterosis.

Evaluation of a set of 10 F hybrids along with their female (27A and 7A) and male parents (C 43, RS 673, RS 627, CB 26, and CB 29) for grain yield and its component traits revealed that grain yield/plant followed by panicle weight, primary branches/panicle, and 100-seed weight exhibited high levels of heterosis. Eight hybrids exhibited 50% or more mid-parent heterosis for grain yield/plant, of which, one hybrid (27A × RS673) recorded heterobeltiosis above 50% (73.61%).

CX3CL1-Fc treatment prevents atherosclerosis in Ldlr KO mice.

Objective: Atherosclerosis is a major cause of cardiovascular disease. Monocyte-endothelial cell interactions are partly mediated by expression of monocyte CX3CR1 and endothelial cell fractalkine (CX3CL1). Interrupting the interaction between this ligand-receptor pair should reduce monocyte binding to the endothelial wall and reduce atherosclerosis.

MET Tyrosine Kinase Inhibition Enhances the Antitumor Efficacy of an HGF Antibody.

Receptor tyrosine kinase therapies have proven to be efficacious in specific cancer patient populations; however, a significant limitation of tyrosine kinase inhibitor (TKI) treatment is the emergence of resistance mechanisms leading to a transient, partial, or complete lack of response. Combination therapies using agents with synergistic activity have potential to improve response and reduce acquired resistance. Chemoreagent or TKI treatment can lead to increased expression of hepatocyte growth factor (HGF) and/or MET, and this effect correlates with increased metastasis and poor prognosis.

Mitochondria COI-based genetic diversity of the cotton leafhopper Amrasca biguttula biguttula (Ishida) populations from India.

Amrasca biguttula biguttula (Ishida), the cotton leafhopper, is a polyphagous insect pest of Asia and Southeast Asian countries. We sequenced a mitochondrial COI gene fragment from 67 individuals of cotton leafhopper collected from 7 major cotton growing states of North, Central, and South India. Genetic divergence analysis of leaf hopper population across India confirmed the presence of single species.

Structure-based optimization of 1H-imidazole-2-carboxamides as Axl kinase inhibitors utilizing a Mer mutant surrogate.

Axl has been a target of interest in the oncology field for several years based on its role in various oncogenic processes. To date, no wild-type Axl crystal structure has been reported. Herein, we describe the structure-based optimization of a novel chemotype of Axl inhibitors, 1H-imidazole-2-carboxamide, using a mutated kinase homolog, Mer(I650M), as a crystallographic surrogate.

Clinical evaluation of Varnya Gana Lepa in Vyanga (melasma).

Background: Vyanga type of Kshudra Roga, characterised by Niruja (painless), Shyava Varna Mandalas (bluish black patches) occurring especially on the face. The clinical features correlate with melasma, which is an acquired chronic hyperpigmentation disorder, usually seen in women of childbearing age. The drugs which constitute the Varnya Gana Lepa bestow the normal Varna (color) by virtue of their qualities and actions.

Biological characterization of TAK-901, an investigational, novel, multitargeted Aurora B kinase inhibitor.

Protein kinases Aurora A, B, and C play essential roles during mitosis and cell division, are frequently elevated in cancer, and represent attractive targets for therapeutic intervention. TAK-901 is an investigational, multitargeted Aurora B kinase inhibitor derived from a novel azacarboline kinase hinge-binder chemotype. TAK-901 exhibited time-dependent, tight-binding inhibition of Aurora B, but not Aurora A.

Development of genic-microsatellite markers for sorghum staygreen QTL using a comparative genomic approach with rice.

The already available comprehensive genome sequence information of model crops along with the transcriptomic resource from other crops provides an excellent opportunity for comparative genome analysis. We studied the synteny between each of the four major sorghum staygreen quantitative trait loci (QTL) regions with that in the rice genome and attempted to increase marker density around the QTL with genic-microsatellites from the sorghum transcriptomic resource using the rice genome as template. For each of the sorghum QTL regions, the reported RFLP markers were compiled, used for sequence similarity searches against the rice genome which identified syntenous regions on rice chromosome 1 for Stg1 and Stg2 QTL, on chromosome 9 for Stg3 QTL, and on chromosome 11 for Stg4 QTL.

Target cell defense prevents the development of diabetes after viral infection.

The mechanisms that regulate susceptibility to virus-induced autoimmunity remain undefined. We establish here a fundamental link between the responsiveness of target pancreatic beta cells to interferons (IFNs) and prevention of coxsackievirus B4 (CVB4)-induced diabetes. We found that an intact beta cell response to IFNs was critical in preventing disease in infected hosts.

A critical role for inducible nitric oxide synthase in host survival following coxsackievirus B4 infection.

Coxsackieviral infections have been linked etiologically to multiple diseases. The serotype CB4 is associated with acute pancreatitis and autoimmune type 1 diabetes. To delineate the mechanisms of host survival after an acute infection with CB4 (strain E2), we have investigated the role of nitric oxide (NO), generated by the inducible form of nitric oxide synthase (NOS2), in viral clearance and pancreatic beta-cell maintenance.

A mechanism for IL-10-mediated diabetes in the nonobese diabetic (NOD) mouse: ICAM-1 deficiency blocks accelerated diabetes.

Neonatal islet-specific expression of IL-10 in nonobese diabetic (NOD) mice accelerates the onset of diabetes, whereas systemic treatment of young NOD mice with IL-10 prevents diabetes. The mechanism for acceleration of diabetes in IL-10-NOD mice is not known. Here we show, by adoptive transfers, that prediabetic or diabetic NOD splenocytes upon encountering IL-10 in the pancreatic islets readily promoted diabetes.

Islet-specific expression of IL-10 promotes diabetes in nonobese diabetic mice independent of Fas, perforin, TNF receptor-1, and TNF receptor-2 molecules.

Several death-signaling or death-inducing molecules have been implicated in beta cell destruction, including Fas, perforin, and TNFR-1. In this study, we examined the role of each death-signaling molecule in the IL-10-accelerated diabetes of nonobese diabetic (NOD) mice. Groups of IL-10-NOD mice, each deficient in either Fas, perforin, or TNFR-1 molecules, readily developed insulitis, and subsequently succumbed to diabetes with an accelerated kinetics and incidence similar to that observed in their wild-type or heterozygous IL-10-NOD littermates.