共查询到20条相似文献,搜索用时 0 毫秒
1.
Mathieu Bibian Ronald J. Rahaim Jun Yong Choi Yoshihiko Noguchi Stephan Schürer Weimin Chen Shima Nakanishi Konstantin Licht Laura H. Rosenberg Lin Li Yangbo Feng Michael D. Cameron Derek R. Duckett John L. Cleveland William R. Roush 《Bioorganic & medicinal chemistry letters》2013,23(15):4374-4380
The development of a series of potent and highly selective casein kinase 1δ/ε (CK1δ/ε) inhibitors is described. Starting from a purine scaffold inhibitor (SR-653234) identified by high throughput screening, we developed a series of potent and highly kinase selective inhibitors, including SR-2890 and SR-3029, which have IC50 ? 50 nM versus CK1δ. The two lead compounds have ?100 nM EC50 values in MTT assays against the human A375 melanoma cell line and have physical, in vitro and in vivo PK properties suitable for use in proof of principle animal xenograft studies against human cancer cell lines. 相似文献
2.
Andrii Monastyrskyi Napon Nilchan Victor Quereda Yoshihiko Noguchi Claudia Ruiz Wayne Grant Michael Cameron Derek Duckett William Roush 《Bioorganic & medicinal chemistry》2018,26(3):590-602
Casein kinase 1δ/ε have been identified as promising therapeutic target for oncology application, including breast and brain cancer. Here, we described our continued efforts in optimization of a lead series of purine scaffold inhibitors that led to identification of two new CK1δ/ε inhibitors 17 and 28 displaying low nanomolar values in antiproliferative assays against the human MDA-MB-231 triple negative breast cancer cell line and have physical, in vitro and in vivo pharmacokinetic properties suitable for use in proof of principle animal xenograft studies against human cancers. 相似文献
3.
Joanne Osborne Kristian Birchall Denise J. Tsagris Stephen J. Lewis Ela Smiljanic-Hurley Debra L. Taylor Alison Levy Dario R. Alessi Edward G. McIver 《Bioorganic & medicinal chemistry letters》2019,29(4):668-673
Parkinson’s disease is a relatively common neurological disorder with incidence increasing with age. Present treatments merely alleviate the symptoms and do not alter the course of the disease, thus identification of disease modifying therapies represents a significant unmet medical need. Mutations in the LRRK2 gene are risk-factors for developing PD and it has been hypothesized that the increased kinase activity of certain LRRK2 mutants are responsible for the damage of the dopaminergic neurons, thus LRRK2 inhibitors offer the potential to target an underlying cause of the disease. In this communication, we describe hit-to-lead medicinal chemistry program on a novel series of 5-azaindazoles. Compound 1, obtained from high-throughput screening was optimized to a highly potent, selective series of molecules with promising DMPK properties. Introduction of heterocycles at the 3-position were found to significantly increase the potency and kinase selectivity, whilst changes to the 4-chlorobenzyl group improved the physicochemical properties. Our series was licensed to a major pharmaceutical company for further development. 相似文献
4.
《Bioorganic & medicinal chemistry letters》2020,30(19):127457
PI3Kδ in B cells mediates antigen receptor signaling and promote neutrophil chemotaxis. The activation of PI3Kδ can cause mast cell maturation and degranulation, myeloid cell dysfunction, and cytokine release. As a key signal molecule, PI3Kδ interacts with the lipid binding domain of a variety of cellular proteins as a secondary messenger, ultimately affecting a series of significant cellular pathways in disease pathology. Therefore, many research organizations and pharmaceutical companies have studied it to develop effectively selective PI3Kδ inhibitors as therapeutics. This review summarizes research advances in varying chemical classes of selective PI3Kδ inhibitors and the structure-activity relationship, and it mainly focuses on the propeller- versus flat-type class of inhibitors. 相似文献
5.
Stephen T. Wrobleski Shuqun Lin T.G. Murali Dhar Alaric J. Dyckman Tianle Li Sidney Pitt Rosemary Zhang Yi Fan Arthur M. Doweyko John S. Tokarski Kevin F. Kish Susan E. Kiefer John S. Sack John A. Newitt Mark R. Witmer Murray McKinnon Joel C. Barrish John H. Dodd Katerina Leftheris 《Bioorganic & medicinal chemistry letters》2013,23(14):4120-4126
A novel series of p38 MAP kinase inhibitors with high selectivity for the p38α isoform over the other family members including the highly homologous p38β isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38α for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38α hinge region. Based on these findings, a general strategy for the rational design of additional promising p38α isoform selective inhibitors by targeting this novel binding mode is proposed. 相似文献
6.
S. Singh I. Jantke M. Simon I. Meybohm B. Boldyreff O. Issinger H. W. Goedde 《Human genetics》1994,93(4):474-474
cDNA probe of the casein kinase 2α subunit gene detects a biallelic PstI polymorphism. This restriction fragment length polymorphism is the first known genetic marker of this gene. 相似文献
7.
8.
Structure–activity relationship of isoform selective inhibitors of Rac1/1b GTPase nucleotide binding
Eric Beausoleil Cédric Chauvignac Thierry Taverne Sandrine Lacombe Laure Pognante Bertrand Leblond Diego Pallares Catherine De Oliveira Florence Bachelot Rachel Carton Hélène Peillon Séverine Coutadeur Virginie Picard Nathalie Lambeng Laurent Désiré Fabien Schweighoffer 《Bioorganic & medicinal chemistry letters》2009,19(19):5594-5598
The synthesis of a series of berberine, phenantridine and isoquinoline derivatives was realized to explore their Rho GTPase nucleotide inhibitory activity. The compounds were evaluated in a nucleotide binding competition assay against Rac1, Rac1b, Cdc42 and in a cellular Rac GTPase activation assay. The insertion of 19 AA in the splice variant Rac1b is shown to be sufficient to introduce a conformational difference that allows compounds 4, 21, 22, and 26 to exhibit selective inhibition of Rac 1b over Rac1. 相似文献
9.
Michael S. Malamas Keith Barnes Yu Hui Matthew Johnson Frank Lovering Jeff Condon William Fobare William Solvibile Jim Turner Yun Hu Eric S. Manas Kristi Fan Andrea Olland Rajiv Chopra Jonathan Bard Menelas N. Pangalos Peter Reinhart Albert J. Robichaud 《Bioorganic & medicinal chemistry letters》2010,20(7):2068-2073
The proteolytic enzyme β-secretase (BACE1) plays a central role in the synthesis of the pathogenic β-amyloid in Alzheimer’s disease. Recently, we reported small molecule acylguanidines as potent BACE1 inhibitors. However, many of these acylguanidines have a high polar surface area (e.g. as measured by the topological polar surface area or TPSA), which is unfavorable for crossing the blood–brain barrier. Herein, we describe the identification of the 2-aminopyridine moiety as a bioisosteric replacement of the acylguanidine moiety, which resulted in inhibitors with lower TPSA values and superior brain penetration. X-ray crystallographic studies indicated that the 2-aminopyridine moiety interacts directly with the catalytic aspartic acids Asp32 and Asp228 via a hydrogen-bonding network. 相似文献
10.
《Bioorganic & medicinal chemistry letters》2020,30(18):127412
The discovery and optimisation of a novel series of potent and selective p38α inhibitors is described. Evaluating the structure-activity relationship of an aminoalkyl substituent at the 3 position of the 2(1H)-pyrazinone core, p38α potency was increased 20000-fold. The most advanced compound (25) demonstrated excellent in vivo properties suitable for an inhaled route of administration. 相似文献
11.
《Bioorganic & medicinal chemistry letters》2020,30(2):126837
Casein kinase 2 catalytic subunit (CK2α) is classified into two subtypes CK2α1 and CK2α2. CK2α1 is a drug discovery target, whereas CK2α2 is an off-target of CK2α1 inhibitors. High amino acid sequence homology between these subtypes hampers efforts to produce ATP competitive inhibitors that are highly selective to CK2α1. Hematein was identified previously as a non-ATP-competitive inhibitor for CK2α1, whereas this compound acts as an ATP competitive CK2α2 inhibitor. Crystal structures of CK2α1 and CK2α2 in complex with hematein revealed distinct binding features that provide structural insights for producing CK2α1-selective inhibitors. 相似文献
12.
Muscle glycogenosis caused by phosphorylase kinase (Phk) deficiency may lead to exercise intolerance, weakness and musculatur atrophy. The gene encoding the muscle isoform of the Phk subunit (M) is one of the candidate genes in which mutations responsible for this condition should be sought. Here, we report the cDNA sequence and the predicted primary structure of the human M subunit. 相似文献
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14.
《Bioorganic & medicinal chemistry》2016,24(5):1136-1141
Two classes of modified analogs of 4-(thiazol-5-yl)benzoic acid-type CK2 inhibitors were designed. The azabenzene analogs, pyridine- and pyridazine-carboxylic acid derivatives, showed potent protein kinase CK2 inhibitory activities [IC50 (CK2α) = 0.014–0.017 μM; IC50 (CK2α′) = 0.0046–0.010 μM]. Introduction of a 2-halo- or 2-methoxy-benzyloxy group at the 3-position of the benzoic acid moiety maintained the potent CK2 inhibitory activities [IC50 (CK2α) = 0.014–0.016 μM; IC50 (CK2α′) = 0.0088–0.014 μM] and led to antiproliferative activities [CC50 (A549) = 1.5–3.3 μM] three to six times higher than those of the parent compound. 相似文献
15.
Jin CH Krishnaiah M Sreenu D Rao KS Subrahmanyam VB Park CY Son JY Sheen YY Kim DK 《Bioorganic & medicinal chemistry》2011,19(8):2633-2640
A series of 1-substituted-3(5)-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)pyrazoles 14a-e, 15a-e, 17a-c, and 18a-d have been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. The 6-quinolinyl pyrazole analogue 14b inhibited ALK5 phosphorylation with IC(50) value of 0.022 μM and showed 84% inhibition at 0.1 μM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct. 相似文献
16.
Fei Li Yunjeong Park Jung-Mi Hah Jae-Sang Ryu 《Bioorganic & medicinal chemistry letters》2013,23(4):1083-1086
A series of 1-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-1,2,3-triazoles has been synthesized and evaluated for their ALK5 inhibitory activity. The 1-(6-methylpyridin-2-yl)-1,2,3-triazoles were assembled by Cu(I)-catalyzed azide–alkyne 1,3-dipolar cycloaddition. Following this, quinoxaline was introduced through Pd-catalyzed direct arylation. The synthesized 1-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-1,2,3-triazoles revealed significant selectivity differences with respect to p38α MAP kinase. In particular, 12k showed 80.8% ALK5 inhibitory activity at a concentration of 10 μM and IC50 value of 4.69 μM, but did not show p38α MAP kinase inhibitory activity (?1.94% inhibition at a concentration of 10 μM). 相似文献
17.
Background
Colorectal cancer (CRC) is one of the most common malignancies but the current therapeutic approaches for advanced CRC are less efficient. Thus, novel therapeutic approaches are badly needed. The purpose of this study is to investigate the involvement of nuclear protein kinase CK2 α subunit (CK2α) in tumor progression, and in the prognosis of human CRC.Methodology/Principal Findings
Expression levels of nuclear CK2α were analyzed in 245 colorectal tissues from patients with CRC by immunohistochemistry, quantitative real-time PCR and Western blot. We correlated the expression levels with clinicopathologic parameters and prognosis in human CRC patients. Overexpression of nuclear CK2α was significantly correlated with depth of invasion, nodal status, American Joint Committee on Cancer (AJCC) staging, degree of differentiation, and perineural invasion. Patients with high expression levels of nuclear CK2α had a significantly poorer overall survival rate compared with patients with low expression levels of nuclear CK2α. In multi-variate Cox regression analysis, overexpression of nuclear CK2α was proven to be an independent prognostic marker for CRC. In addition, DLD-1 human colon cancer cells were employed as a cellular model to study the role of CK2α on cell growth, and the expression of CK2α in DLD-1 cells was inhibited by using siRNA technology. The data indicated that CK2α-specific siRNA treatment resulted in growth inhibition.Conclusions/Significance
Taken together, overexpression of nuclear CK2α can be a useful marker for predicting the outcome of patients with CRC. 相似文献18.
Michael S. Malamas Keith Barnes Matthew Johnson Yu Hui Ping Zhou Jim Turner Yun Hu Erik Wagner Kristi Fan Rajiv Chopra Andrea Olland Jonathan Bard Menelas Pangalos Peter Reinhart Albert J. Robichaud 《Bioorganic & medicinal chemistry》2010,18(2):630-639
The identification of highly selective small molecule di-substituted pyridinyl aminohydantoins as β-secretase inhibitors is reported. The more potent and selective analogs demonstrate low nanomolar potency for the BACE1 enzyme as measured in a FRET assay, and exhibit comparable activity in a cell-based (ELISA) assay. In addition, these pyridine-aminohydantoins are highly selectivity (>500×) against the other structurally related aspartyl proteases BACE2, cathepsin D, pepsin and renin.Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on the previously reported aminohydantoin 3a. We have taken advantage of the amino acid difference between the BACE1 and BACE2 at the S2′ pocket (BACE1 Pro70 changed to BACE2 Lys86) to build ligands with >500-fold selectivity against BACE2. The addition of large substituents on the targeted ligand at the vicinity of this aberration has generated a steric conflict between the ligand and these two proteins, thus impacting the ligand’s affinity and selectivity. These ligands have also shown an exceptional selectivity against cathepsin D (>5000-fold) as well as the other aspartyl proteases mentioned. One of the more potent compounds (S)-39 displayed an IC50 value for BACE1 of 10 nM, and exhibited cellular activity with an EC50 value of 130 nM in the ELISA assay. 相似文献
19.
John I. Trujillo James R. Kiefer Wei Huang Atli Thorarensen Li Xing Nicole L. Caspers Jacqueline E. Day Karl J. Mathis Kuniko K. Kretzmer Beverley A. Reitz Robin A. Weinberg Roderick A. Stegeman Ann Wrightstone Lori Christine Robert Compton Xiong Li 《Bioorganic & medicinal chemistry letters》2009,19(3):908-911
The inhibition of PKC-ζ has been proposed to be a potential drug target for immune and inflammatory diseases. A series of 2-(6-phenyl-1H indazol-3-yl)-1H-benzo[d]imidazoles with initial high crossover to CDK-2 has been optimized to afford potent and selective inhibitors of protein kinase c-zeta (PKC-ζ). The determination of the crystal structures of key inhibitor:CDK-2 complexes informed the design and analysis of the series. The most selective and potent analog was identified by variation of the aryl substituent at the 6-position of the indazole template to give a 4-NH2 derivative. The analog displays good selectivity over other PKC isoforms (α, βII, γ, δ, ε, μ, θ, η and ι/λ) and CDK-2, however it displays marginal selectivity against a panel of other kinases (37 profiled). 相似文献
20.
《Bioorganic & medicinal chemistry letters》2014,24(15):3412-3418
The synthesis and structure–activity relationships of novel 4-(4′-fluorophenyl)imidazoles as selective p38α MAPK, CK1δ and JAK2 inhibitors with improved water solubility are described. Microwave-assisted multicomponent reactions afforded 4-fluorophenyl-2,5-disubstituted imidazoles. Carboxylate and phosphonate groups were introduced via ‘click’ reactions. The kinase selectivity was influenced by the heteroaryl group at imidazole C-5 and the position of a carboxylic acid or tetrazole at imidazole C-2. For example, pyrimidines 15 and 34 inhibited p38α MAPK with IC50 = 250 nM and 96 nM, respectively. Pyridine 3 gave CK1δ inhibition with IC50 = 89 nM and pyridin-2-one 31 gave JAK2 inhibition with IC50 = 62 nM. 相似文献