Browse
Submit Data
Databases
API
Help

Dataset Information

34 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Discovery of Substituted 1H-Pyrazolo[3,4-b]pyridine Derivatives as Potent and Selective FGFR Kinase Inhibitors.

ABSTRACT: Fibroblast growth factor receptors (FGFRs) are important targets for cancer therapy. Herein, we describe the design, synthesis, and biological evaluation of a novel series of 1H-pyrazolo[3,4-b]pyridine derivatives as potent and selective FGFR kinase inhibitors. On the basis of its excellent in vitro potency and favorable pharmacokinetic properties, compound 7n was selected for in vivo evaluation and showed significant antitumor activity in a FGFR1-driven H1581 xenograft model. These results indicated that 7n would be a promising candidate for further drug development.

SUBMITTER: Zhao B

PROVIDER: S-EPMC4904267 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Discovery of Substituted 1H-Pyrazolo[3,4-b]pyridine Derivatives as Potent and Selective FGFR Kinase Inhibitors.

Zhao Bin B Li Yixuan Y Xu Pan P Dai Yang Y Luo Cheng C Sun Yiming Y Ai Jing J Geng Meiyu M Duan Wenhu W

ACS medicinal chemistry letters 20160420 6

Fibroblast growth factor receptors (FGFRs) are important targets for cancer therapy. Herein, we describe the design, synthesis, and biological evaluation of a novel series of 1H-pyrazolo[3,4-b]pyridine derivatives as potent and selective FGFR kinase inhibitors. On the basis of its excellent in vitro potency and favorable pharmacokinetic properties, compound 7n was selected for in vivo evaluation and showed significant antitumor activity in a FGFR1-driven H1581 xenograft model. These results indi ...[more]

PMID: 27326339

Similar Datasets

Identification of 1H-pyrazolo[3,4-b]pyridine derivatives as potent ALK-L1196M inhibitors.

Project description:Anaplastic lymphoma kinase (ALK) has been recognised as a promising molecular target of targeted therapy for NSCLC. We performed SAR study of pyrazolo[3,4-b]pyridines to override crizotinib resistance caused by ALK-L1196M mutation and identified a novel and potent L1196M inhibitor, 10g. 10g displayed exceptional enzymatic activities (<0.5?nM of IC50) against ALK-L1196M as well as against ALK-wt. In addition, 10g is an extremely potent inhibitor of ROS1 (<0.5?nM of IC50) and displays excellent selectivity over c-Met. Moreover, 10g strongly suppresses proliferation of ALK-L1196M-Ba/F3 and H2228 cells harbouring EML4-ALK via apoptosis and the ALK signalling blockade. The results of molecular docking studies reveal that, in contrast to crizotinib, 10g engages in a favourable interaction with M1196 in the kinase domain of ALK-L1196M and hydrogen bonding with K1150 and E1210. This SAR study has provided a useful insight into the design of novel and potent inhibitors against ALK gatekeeper mutant.

| S-EPMC6713165 | biostudies-literature

Structural Basis for PPAR? Activation by 1H-pyrazolo-[3,4-b]pyridine Derivatives.

Project description:Small-molecule agonism of peroxisome proliferator-activated receptor ? (PPAR?), a ligand-activated transcriptional factor involved in regulating fatty acid metabolism, is an important approach for treating dyslipidemia. Here, we determined the structures of the ligand-binding domain (LBD) of PPAR? in complex with 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid derivatives, which were recently identified as PPAR?-selective activators with markedly different structures from those of the well-known PPAR? agonists fibrates. The crystal structures of the complexes showed that they form a canonical hydrogen-bond network involving helix 12 in the LBD, which is thought to be essential for PPAR? activation, as also observed for fibrates. However, the phenyl side chain of the compounds occupies a small cavity between Ile272 and Ile354, which is rarely accessed by fibrates. This unique feature may be essential for subtype selectivity and combine with the well-characterized binding mode of fibrates to improve activity. These findings demonstrate the advantage of using 1H-pyrazolo-[3,4-b]pyridine as a skeleton of PPAR? agonists and provide insight into the design of molecules for treating dyslipidemia.

| S-EPMC7203124 | biostudies-literature

3-Iodo-1H-pyrazolo-[3,4-b]pyridine.

Project description:The title compound, C6H4IN3, is essentially planar, with a dihedral angle of 0.82?(3)° between the planes of the pyridine and pyrazole rings. In the crystal, pairs of mol-ecules are connected into inversion dimers through N-H?N hydrogen bonds. C-I?N halogen bonds link the dimers into zigzag chains parallel to the b-axis direction. The packing also features ?-? stacking inter-actions along (110) with inter-planar distances of 3.292?(1) and 3.343?(1)?Å, and centroid-centroid distances of 3.308?(1) and 3.430?(1)?Å.

| S-EPMC4051060 | biostudies-literature

3,4,6-Trimethyl-1-phenyl-1H-pyrazolo-[3,4-b]pyridine.

Project description:In the title compound, C(15)H(15)N(3), the 1H-pyrazolo-[3,4-b]pyridine system and the phenyl ring are each individually planar, with r.m.s. deviations of 0.017?(2) and 0.011?(2)?Å, respectively; the dihedral angle between the two aromatic systems is 9.33?(10)°. The crystal packing is stabilized by offset ?-? stacking between parallel pyrazolo-[3,4-b]pyridine ring systems [face-to-face distance = 3.449?(6)?Å].

| S-EPMC3007300 | biostudies-literature

Four-component bicyclization approaches to skeletally diverse pyrazolo[3,4-b]pyridine derivatives.

Project description:A novel four-component bicyclization strategy has been established, allowing a flexible and practical approach to 37 examples of multicyclic pyrazolo[3,4-b]pyridines from low-cost and readily accessible arylglyoxals, pyrazol-5-amines, aromatic amines, 4-hydroxy-6-methyl-2H-pyran-2-one, and cyclohexane-1,3-diones. The polysubstituted cyclopenta[d]pyrazolo[3,4-b]pyridines were stereoselectively synthesized through a microwave-assisted special [3+2+1]/[3+2] bicyclization with good control of the spatial configuration of exocyclic double bonds. The novel [3+2+1]/[2+2+1] bicyclization resulted in 17 examples of unreported pyrazolo[3,4-b]pyrrolo[4,3,2-de]quinolones. Reasonable mechanisms for forming two new types of multicyclic pyrazolo[3,4-b]pyridines are also proposed.

| S-EPMC4242041 | biostudies-literature

Design, synthesis and biological evaluation of pyrazolo[3,4-<i>d</i>]pyridazinone derivatives as covalent FGFR inhibitors.

Project description:Fibroblast growth factor receptors (FGFRs) have emerged as promising targets for anticancer therapy. In this study, we synthesized and evaluated the biological activity of 66 pyrazolo[3,4-d]pyridazinone derivatives. Kinase inhibition, cell proliferation, and whole blood stability assays were used to evaluate their activity on FGFR, allowing us to explore structure-activity relationships and thus to gain understanding of the structural requirements to modulate covalent inhibitors' selectivity and reactivity. Among them, compound 10h exhibited potent enzymatic activity against FGFR and remarkably inhibited proliferation of various cancer cells associated with FGFR dysregulation, and suppressed FGFR signaling pathway in cancer cells by the immunoblot analysis. Moreover, 10h displayed highly potent antitumor efficacy (TGI = 91.6%, at a dose of 50 mg/kg) in the FGFR1-amplified NCI-H1581 xenograft model.

| S-EPMC7982429 | biostudies-literature

Synthesis, Cyclooxygenases Inhibition Activities and Interactions with BSA of N-substituted 1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones Derivatives.

Project description:Inhibition of cyclooxygenase is the way of therapeutic activities for anti-inflammatory pharmaceuticals. Serum albumins are the major soluble protein able to bind and transport a variety of exogenous and endogenous ligands, including hydrophobic pharmaceuticals. In this study, a novel N-substituted 1H-pyrrolo[3-c]pyridine-1,3(2H)-diones derivatives were synthesized and biologically evaluated for their inhibitory activity against cyclooxygenases and interactions with BSA. In vitro, COX-1 and COX-2 inhibition assays were performed. Interaction with BSA was studied by fluorescence spectroscopy and circular dichroism measurement. The molecular docking study was conducted to understand the binding interaction of compounds in the active site of cyclooxygenases and BSA. The result of the COX-1 and COX-2 inhibitory studies revealed that all the compounds potentially inhibited COX-1 and COX-2. The IC50 value was found similar to meloxicam. The intrinsic fluorescence of BSA was quenched by tested compounds due to the formation of A/E-BSA complex. The results of the experiment and molecular docking confirmed the main interaction forces between studied compounds and BSA were hydrogen bonding and van der Waals force.

| S-EPMC7355801 | biostudies-literature

Discovery of N-[4-(1H-Pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-sulfonamides as Highly Active and Selective SGK1 Inhibitors.

Project description:From a virtual screening starting point, inhibitors of the serum and glucocorticoid regulated kinase 1 were developed through a combination of classical medicinal chemistry and library approaches. This resulted in highly active small molecules with nanomolar activity and a good overall in vitro and ADME profile. Furthermore, the compounds exhibited unusually high kinase and off-target selectivity due to their rigid structure.

| S-EPMC4291729 | biostudies-literature

Screening of Heteroaromatic Scaffolds against Cystathionine Beta-Synthase Enables Identification of Substituted Pyrazolo[3,4-c]Pyridines as Potent and Selective Orthosteric Inhibitors.

Project description:Cystathionine ?-synthase (CBS) is a key enzyme in the production of the signaling molecule hydrogen sulfide, deregulation of which is known to contribute to a range of serious pathological states. Involvement of hydrogen sulfide in pathways of paramount importance for cellular homeostasis renders CBS a promising drug target. An in-house focused library of heteroaromatic compounds was screened for CBS modulators by the methylene blue assay and a pyrazolopyridine derivative with a promising CBS inhibitory potential was discovered. The compound activity was readily comparable to the most potent CBS inhibitor currently known, aminoacetic acid, while a promising specificity over the related cystathionine ?-lyase was identified. To rule out any possibility that the inhibitor may bind the enzyme regulatory domain due to its high structural similarity with cofactor s-adenosylmethionine, differential scanning fluorimetry was employed. A sub-scaffold search guided follow-up screening of related compounds, providing preliminary structure-activity relationships with respect to requisites for efficient CBS inhibition by this group of heterocycles. Subsequently, a hypothesis regarding the exact binding mode of the inhibitor was devised on the basis of the available structure-activity relationships (SAR) and a deep neural networks analysis and further supported by induced-fit docking calculations.

| S-EPMC7465669 | biostudies-literature

4-Benzyl-sulfanyl-1H-pyrazolo-[3,4-d]pyrimidine.

Project description:The pyrazolo-[3,4-d]pyrimidine ring system of the title compound, C12H10N4S, is essentially planar [maximum deviation = 0.025?(1)?Å for the C atom bearing the S atom] and almost perpendicular to the phenyl ring [dihedral angle = 71.42?(6)°]. In the crystal, mol-ecules are linked via pairs of N-H?N hydrogen bonds, forming inversion dimers.

| S-EPMC3884315 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data