A5077315674- Neuropeptides and Animal Physiology
- Diabetes Treatment and Management
- Computational Drug Discovery Methods
- Peptidase Inhibition and Analysis
- Angiogenesis and VEGF in Cancer
- Enzyme function and inhibition
- Biochemical Analysis and Sensing Techniques
- HER2/EGFR in Cancer Research
- Chemical Synthesis and Analysis
- Click Chemistry and Applications
- Peroxisome Proliferator-Activated Receptors
- Biotechnology and Related Fields
- Cardiomyopathy and Myosin Studies
- Liver physiology and pathology
- Receptor Mechanisms and Signaling
- Cell death mechanisms and regulation
- Cellular Mechanics and Interactions
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Lipid metabolism and biosynthesis
- Biotin and Related Studies
- Monoclonal and Polyclonal Antibodies Research
- Carbon dioxide utilization in catalysis
- Muscle Physiology and Disorders
- Regulation of Appetite and Obesity
- PI3K/AKT/mTOR signaling in cancer
Takeda (Japan)
2011-2023
// Kazuhide Nakayama 1, * , Magdalena M. Szewczyk 2, Carlo dela Sena Hong Wu 2 Aiping Dong Zeng Fengling Li Renato Ferreira de Freitas Mohammad S. Eram Matthieu Schapira 3 Yuji Baba 1 Mihoko Kunitomo Douglas R. Cary Michiko Tawada 4 Akihiro Ohashi Yasuhiro Imaeda Kumar Singh Saikatendu 5 Charles E. Grimshaw 6 Masoud Vedadi Cheryl H. Arrowsmith 7 Dalia Barsyte-Lovejoy Atsushi Kiba Daisuke Tomita and Peter J. Brown Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Company...
Mcl-1 and Bcl-xL are crucial regulators of apoptosis, therefore dual inhibitors both proteins could serve as promising new anticancer drugs. To design Mcl-1/Bcl-xL inhibitors, we performed structure-guided analyses the corresponding selective inhibitors. A cocrystal structure a pyrazolo[1,5-a]pyridine derivative with protein was successfully determined revealed protein–ligand binding mode. The key for inhibition further confirmed through substructural analysis ABT-263, representative...
Benzoxazepinones have been extensively studied as exclusively selective RIP kinase 1 inhibitors. This scaffold binds a type-III inhibitor targeting the αC-out/DFG-out conformation. inactive conformation results in large expansion of back pocket, that has also reported for LIM kinases. Scaffold hopping is common design orthosteric inhibitors, but not explored allosteric mainly due to typically exclusive selectivity type III Here, we hypothesized shared structural properties LIMKs and RIPKs...
A novel series of non-amidine-based C1s inhibitors have been explored. Starting from high-throughput screening hit 3, isoquinoline was replaced with 1-aminophthalazine to enhance inhibitory activity while exhibiting good selectivity against other serine proteases. We first disclose a crystal structure complex and small-molecule inhibitor (4e), which guided structure-based optimization around the S2 S3 sites further by over 300-fold. Improvement membrane permeability incorporation fluorine at...
We present a straightforward process for the discovery of novel back pocket-binding fragment molecules against protein tyrosine kinases. The approach begins by screening nonphosphorylated target kinase with subsequent counterscreening hits phosphorylated enzyme. Back fragments are inactive kinase. Fragment insufficient size to span both regions ATP binding pocket; thus, outcome is binary (back or hinge-binding). Next, appropriate profile assayed in combination known hinge-binding and...
The action of the aspartyl protease renin is rate-limiting initial step renin-angiotensin-aldosterone system. Therefore, a particularly promising target for blood pressure as well onset and progression cardiovascular renal diseases. New pyrimidine derivatives 5-14 were designed in an attempt to enhance inhibitory activity compound 3 identified by our previous fragment-based drug design approach. Introduction basic amine essential interaction with two aspartic acids catalytic site...
The DEAD-box family of RNA helicases plays essential roles in both transcriptional and translational mRNA degradation; they unwind short double-stranded by breaking the RNA-RNA interactions. Two helicases, eukaryotic translation initiation factor 4A3 (eIF4A3) helicase 3 (DDX3X), show high homology ATP-binding region are considered key molecules for cancer progression. Several small that target eIF4A3 DDX3X have been reported to inhibit cell growth; however, more potent compounds required...
O-GlcNAcase (OGA) has received increasing attention as an attractive therapeutic target for tau-mediated neurodegenerative disorders; however, its role in these pathologies remains unclear. Therefore, potent chemical tools with favorable pharmacokinetic profiles are desirable to characterize this enzyme. Herein, we report the discovery of a and novel OGA inhibitor, compound 5i, comprising aminopyrimidine scaffold, identified by virtual screening based on multiple methodologies combining...
Dysferlinopathies, which are muscular diseases caused by mutations in the dysferlin gene, remain serious medical problems due to lack of therapeutic agents. Herein, we report design, synthesis, and structure-activity relationships a 2,6-disubstituted 3H-imidazo[4,5-b]pyridine series, was identified from phenotypic screening chemicals that increase level myocytes differentiated patient-derived induced pluripotent stem cells (iPSCs). Optimization studies with cell-based assay led...
Synthetic organic chemistry is a core technology of drug discovery, but combined with in silico which consists molecular modeling and/or informatics using computational methods, it can be expected to accelerate discovery research and increase the success rate for developing new drug. However, cannot create drugs by itself, its integration necessary. In this paper, we describe that effectively integrates develop synthetic strategies efficiently novel lead compound or vivo tool.