Potent P38α Inhibitors Research Articles

Fragment-Based Structural Optimization of a Natural Product Itampolin A as a p38α Inhibitor for Lung Cancer.

Marine animals and plants provide abundant secondary metabolites with antitumor activity. Itampolin A is a brominated natural tyrosine secondary metabolite that is isolated from the sponge Iotrochota purpurea. Recently, we have achieved the first total synthesis of this brominated tyrosine secondary metabolite, which was found to be a potent p38α inhibitor exhibiting anticancer effects. A fragment-based drug design (FBDD) was carried out to optimize itampolin A. Forty-five brominated tyrosine derivatives were synthesized with interesting biological activities. Then, a QSAR study was carried out to explore the structural determinants responsible for the activity of brominated tyrosine skeleton p38α inhibitors. The lead compound was optimized by a FBDD method, then three series of brominated tyrosine derivatives were synthesized and evaluated for their inhibitory activities against p38α and tumor cells. Compound 6o (IC50 = 0.66 μM) exhibited significant antitumor activity against non-small cell lung A549 cells (A549). This also demonstrated the feasibility of the FBDD method of structural optimization.

Graph Theoretical Analysis, Insilico Modeling and Formulation of Pyrimidine Nanoparticles as p38α MAP Kinases inhibitors: A Quantitative Proteomics Approach.

In this study, the optimized 4-(4-hydroxybenzyl)-2-amino-6-hydroxypyrimidine-5-carboxamide derivative was formulated as nanoparticles to evaluate for their anticancer activity. The response surface methodology (RSM) was performed with utilization of Box-Behnken statistical design (BBSD) to optimize the experimental conditions for identification of significant synthetic methodology. To explore the stability of the derivative was done by density functional theory (DFT). Graph theoretical analysis was introduced to identify the drug target p38α MAP Kinases and then insilico modeling was performed to provide straightforward information for further structural optimization. The experimental results under optimal experimental conditions obtained 74.55-76% yield of 4-(4-hydroxybenzyl)-2-amino-6-hydroxypyrimidine-5-carboxamide, 127oC melting point and Rf value 0.59 were well matched with the predicted results and this was gaining 95% of confidence level and suitability of RSM. The spectral data were reliable with the assigned structures of synthetic yields. The formulated nanoparticles were exhibited a good anticancer activity against used cancer cell line MCF7. Amusingly the observed docking scores and in-vitro anticancer activity was proving the compound significance and potential as a potent p38α inhibitor. Further, we have elucidated the mechanism of action at its functional level using label-free quantitative proteomics. Interestingly the observed results were indicating that the derived proteomics data involving in the alteration process in cancer-related regulatory pathways.

Targeting the Hinge Glycine Flip and the Activation Loop: Novel Approach to Potent p38α Inhibitors

The p38 MAP kinase is a key player in signaling pathways regulating the biosynthesis of inflammatory cytokines. Small molecule p38 inhibitors suppress the production of these cytokines. Therefore p38 is a promising drug target for novel anti-inflammatory drugs. In this study, we report novel dibenzepinones, dibenzoxepines, and benzosuberones as p38α MAP kinase inhibitors. Previously reported dibenzepinones and dibenzoxepines were chemically modified by introduction of functional groups or removal of a phenyl ring. This should result in targeting of the hydrophobic region I, the "deep pocket", and the hinge glycine flip of the kinase. Potent inhibitors with IC(50) values in the single digit nanomolar range (up to 3 nM) were identified. Instead of targeting the "deep pocket" in the DFG-out conformation, interactions with the DFG-motif in the in-conformation could be observed by protein X-ray crystallography.

Insight into the Structural Determinants of Imidazole Scaffold-Based Derivatives as P38 MAP Kinase Inhibitors by Computational Explorations

P38 kinase plays a vital role in the inflammation mediated by tumor necrosis factor-α and interleukin-1β pathways, and thus the inhibitors of p38 kinase provide effective approach for the treatment of inflammatory diseases. Presently, a combined study of three-dimensional quantitative structure-activity relationship, molecular docking and molecular dynamics (MD) was undertaken to explore the structural insights of 174 2-thioimidazole compounds influencing the p38α inhibitory activities. Both the ligand-based resultant comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models exhibited satisfactory predictability (with Q(2)=0.475, R(2)(ncv)=0.774, R(2)(pre)=0.668 and Q(2)=0.504, R(2)(ncv)=0.745, R(2)(pre)=0.709, respectively). Furthermore, good consistency was observed between the 3D-QSAR models, docking and MD results. Our findings are: i) hydrogen bonding and steric size of the molecules play crucial roles in the mechanisms of action that a medium-sized bulky substituent on the 2-position, an electropositive H-bond donor substituent on the 6-position of the pyridine ring are favorable for increasing the inhibition activity; ii) 2- Thioimidazole derivatives may bind to the p38α kinase with a "lobster" active conformation, which is fixed by four hydrogen bonds they formed with the adjacent residues (Lys53, Gly110, Met109 and Ala157) and two hydrophobic interactions (in hydrophobic pockets I and II respectively) in p38α binding site. These models and the derived information may afford valuable clues for design of new potent p38α inhibitors.

Design and synthesis of novel p38α MAP kinase inhibitors: Discovery of pyrazole-benzyl ureas bearing 2-molpholinopyrimidine moiety

The discovery that pyrazole-benzyl urea derivatives bearing a 2-molpholinopyrimidine moiety are novel p38α inhibitors is described. A comparative view of the binding modes of SB-203580 and BIRB-796 by structural alignment of two X-ray co-crystal structures was utilized to identify this novel series. Modification of the benzyl group led to compound 2b, a highly potent p38α inhibitor. In in vivo studies, 2b inhibited the production of tumor necrosis factor-alpha in lipopolysaccharide-treated mouse in a dose-dependent manner. Furthermore, the results of a 5-day repeated oral dose toxicity study suggest that 2b has low hepatotoxicity.

Identification of triazolopyridazinones as potent p38α inhibitors

Structure-activity relationship (SAR) investigations of a novel class of triazolopyridazinone p38α mitogen activated protein kinase (MAPK) inhibitors are disclosed. From these studies, increased in vitro potency was observed for 2,6-disubstituted phenyl moieties and N-ethyl triazolopyridazinone cores due to key contacts with Leu108, Ala157 and Val38. Further investigation led to the identification of three compounds, 3g, 3j and 3m that are highly potent inhibitors of LPS-induced MAPKAP kinase 2 (MK2) phosphorylation in 50% human whole blood (hWB), and possess desirable in vivo pharmacokinetic and kinase selectivity profiles.

1,7-Naphthyridine 1-Oxides as Novel Potent and Selective Inhibitors of p38 Mitogen Activated Protein Kinase

The design, synthesis, and ability to inhibit p38α MAP kinase by a novel series of naphthyridine N-oxides will be described. Some of these compounds showed a significant reduction in the LPS-induced TNFα production in human whole blood. Structure-activity relationship studies revealed that N-oxide oxygen was essential for activity and was probably a determinant factor for its marked selectivity against other related kinases. After an extensive SAR exercise, several compounds from this series were identified as very potent p38α inhibitors. In vivo efficacy of some derivatives was demonstrated to reduce TNFα levels in an acute murine model of inflammation (ED(50) = 0.5 mg/kg in LPS-induced TNFα production when dosed orally 1.5 h prior to LPS administration). The oral efficacy was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally (ED(50) < 1 mg/kg).

ChemInform Abstract: 5‐Amino‐pyrazoles as Potent and Selective p38α Inhibitors.

AbstractExtensive SAR studies on p38α MAP kinase inhibitors based on a 5‐aminopyrazole scaffold result in the identification of compound (I) as one of the most potent p38α inhibitor with single digit nanomolar potency for the inhibition of TNF‐α release in human peripheral blood mononuclear cells.

Biological Evaluation and Structural Determinants of p38α Mitogen‐Activated‐Protein Kinase and c‐Jun‐N‐Terminal Kinase 3 Inhibition by Flavonoids

A series of 42 naturally occurring flavonoids and one flavonoid glucuronide were tested for their ability to inhibit p38α mitogen-activated protein kinase (p38α) and c-Jun-N-terminal kinase 3 (JNK3). Potent inhibitors with IC(50) values in the low micromolar range were identified. Structure-activity relationships were evaluated and the most promising compounds were docked into the ATP binding site of these kinases. Among the different classes of flavonoids, the flavonol group showed better inhibition of p38α. Of this class, kaempferol-7,4'-dimethylether was a potent p38α inhibitor, displaying 13-fold selectivity for p38α over JNK3. The flavone compounds without a 6-methoxy group preferentially inhibited JNK3. The flavone glycoside, luteolin-7-O-glycoside, was identified as a potent inhibitor with the greatest selectivity toward JNK3. In contrast, the flavanol compounds displayed similar inhibitory activities toward both kinases.

Utilization of a nitrogen–sulfur nonbonding interaction in the design of new 2-aminothiazol-5-yl-pyrimidines as p38α MAP kinase inhibitors

The design, synthesis, and structure–activity relationships (SAR) of a series of 2-aminothiazol-5-yl-pyrimidines as novel p38α MAP kinase inhibitors are described. These efforts led to the identification of 41 as a potent p38α inhibitor that utilizes a unique nitrogen–sulfur intramolecular nonbonding interaction to stabilize the conformation required for binding to the p38α active site. X-ray crystallographic studies that confirm the proposed binding mode of this class of inhibitors in p38α and provide evidence for the proposed intramolecular nitrogen–sulfur interaction are discussed.

Pyrazoloheteroaryls: Novel p38α MAP kinase inhibiting scaffolds with oral activity

A test library with three novel p38α inhibitory scaffolds and a narrow set of substituents was prepared. Appropriate combination of substituent and scaffold generated potent p38α inhibitors, for example, pyrazolo[3,4- b]pyridine 9, pyrazolo[3,4- d]pyrimidine 18a and pyrazolo[3,4- b]pyrazine 23b with potent in vivo activity upon oral administration in animal models of rheumatoid arthritis.