共查询到20条相似文献,搜索用时 31 毫秒
1.
Hui Qiu Lesley Liu-Bujalski Richard D Caldwell Ariele Viacava Follis Anna Gardberg Andreas Goutopoulos Roland Grenningloh Jared Head Theresa Johnson Reinaldo Jones Igor Mochalkin Federica Morandi Constantin Neagu Brian Sherer 《Bioorganic & medicinal chemistry letters》2018,28(17):2939-2944
Bruton's Tyrosine Kinase (BTK) is a member of the TEC kinase family that is expressed in cells of hematopoietic lineage (e.g., in B cells, macrophages, monocytes, and mast cells). Small molecule covalent irreversible BTK inhibitor targeting Cys481 within the ATP-binding pocket, for example ibrutinib, has been applied in the treatment of B-cell malignancies. Starting from a fragment hit, we discovered a novel series of potent covalent irreversible BTK inhibitors that occupy selectivity pocket of the active site of the BTK kinase domain. Guided by X-ray structures and a fragment-based drug design (FBDD) approach, we generated molecules showing comparable cellular potency to ibrutinib and higher kinome selectivity against undesirable off-targets like EGFR. 相似文献
2.
Simeon Bowers Ying-zi Xu Shendong Yuan Gary D. Probst Roy K. Hom Wayman Chan Andrei W. Konradi Hing L. Sham Yong L. Zhu Paul Beroza Hu Pan Eric Brecht Nanhua Yao Julie Lougheed Danny Tam Zhao Ren Lany Ruslim Michael P. Bova Dean R. Artis 《Bioorganic & medicinal chemistry letters》2013,23(7):2181-2186
The structure–activity relationship of a series of dihydroisoquinoline BACE-1 inhibitors is described. Application of structure-based design to screening hit 1 yielded sub-micromolar inhibitors. Replacement of the carboxylic acid of 1 was guided by X-ray crystallography, which allowed the replacement of a key water-mediated hydrogen bond. This work culminated in compounds such as 31, which possess good BACE-1 potency, excellent permeability and a low P-gp efflux ratio. 相似文献
3.
Linyi Liu Bingyu Shi Xinyu Li Xiangqian Wang Xiang Lu Xuerong Cai Ali Huang Guoshun Luo Qidong You Hua Xiang 《Bioorganic & medicinal chemistry》2018,26(15):4537-4543
Btk inhibitors and PI3Kδ inhibitors play crucial roles in the treatment of leukemia, and studies confirmed that the synergetic inhibition against Btk and PI3Kδ could gain an optimal response. Herein, a series of novel benzofuro[3,2-b]pyridin-2(1H)-one derivatives were designed and synthesized as dual Btk/PI3Kδ kinases inhibitors for the treatment of leukemia. Studies indicated that most compounds could suppress the proliferation of multiple leukemia or lymphoma cells (Raji, HL60 and K562 cells) at low micromolar concentrations in vitro. Further kinase assays identified several compounds could simultaneously inhibit Btk kinase and PI3Kδ kinase. Thereinto, compound 16b exhibited the best inhibitory activity (Btk: IC50?=?139?nM; PI3Kδ: IC50?=?275?nM) and showed some selectivity against PI3Kδ compared to PI3Kβ/γ. Finally, the SAR of target compounds was preliminarily discussed combined with docking results. In brief, 16b possessed of the potency for the further optimization as anti-leukemia drugs by inhibiting simultaneously Btk kinase and PI3Kδ kinase. 相似文献
4.
5.
Youseung Shin Weiming Chen Jeff Habel Derek Duckett Yuan Yuan Ling Marcel Koenig Yuanjun He Tomas Vojkovsky Philip LoGrasso Theodore M. Kamenecka 《Bioorganic & medicinal chemistry letters》2009,19(12):3344-3347
A novel series of c-jun N-terminal kinase (JNK) inhibitors were designed and developed from a high-throughput-screening hit. Through the optimization of the piperazine amide 1, several potent compounds were discovered. The X-ray crystal structure of 4g showed a unique binding mode different from other well known JNK3 inhibitors. 相似文献
6.
Richard Caldwell Lesley Liu-Bujalski Hui Qiu Igor Mochalkin Reinaldo Jones Constantin Neagu Andreas Goutopoulos Roland Grenningloh Theresa Johnson Brian Sherer Anna Gardberg Ariele Viacava Follis Federica Morandi Jared Head 《Bioorganic & medicinal chemistry letters》2018,28(21):3419-3424
Btk is an attractive target for the treatment of a range of Bcell malignancies as well as several autoimmune diseases such as murine lupus and rheumatoid arthritis. Several covalent irreversible inhibitors of Btk are currently in development including ibrutinib which was approved for treatment of B-cell malignancies. Herein, we describe our efforts using X-ray guided structure based design (SBD) to identify a novel chemical series of covalent Btk inhibitors. The resulting pyridine carboxamides were potent and selective inhibitors of Btk having excellent enzymatic and cellular inhibitory activity. 相似文献
7.
《Bioorganic & medicinal chemistry》2020,28(6):115353
A series of sirtuin inhibitor candidates were assembled based on an intermediate ester (1a) our accidently discovered. After screening and evaluation, several SIRT2 selective inhibitors were identified, which can inhibit all the deacetylation, defatty-acylation and debenzoylation of SIRT2. Among these inhibitors, compound 1e was the best SIRT2 selective inhibitors. The primary study on the inhibitory mechanism indicated that compound 1e may be a suicide inhibitor acting as an irreversible way. Given almost all reported sirtuin inhibitors are non-covalent, sirtuin covalent inhibitors are still need to be developed. These findings will facilitate for further development of SIRT2 selective and suicide inhibitors. 相似文献
8.
John D. Harling Angela M. Deakin Sébastien Campos Rachel Grimley Laiq Chaudry Catherine Nye Oxana Polyakova Christina M. Bessant Nick Barton Don Somers John Barrett Rebecca H. Graves Laura Hanns William J. Kerr Roberto Solari 《The Journal of biological chemistry》2013,288(39):28195-28206
IL-2-inducible tyrosine kinase (Itk) plays a key role in antigen receptor signaling in T cells and is considered an important target for anti-inflammatory drug discovery. In order to generate inhibitors with the necessary potency and selectivity, a compound that targeted cysteine 442 in the ATP binding pocket and with an envisaged irreversible mode of action was designed. We incorporated a high degree of molecular recognition and specific design features making the compound suitable for inhaled delivery. This study confirms the irreversible covalent binding of the inhibitor to the kinase by x-ray crystallography and enzymology while demonstrating potency, selectivity, and prolonged duration of action in in vitro biological assays. The biosynthetic turnover of the kinase was also examined as a critical factor when designing irreversible inhibitors for extended duration of action. The exemplified Itk inhibitor demonstrated inhibition of both TH1 and TH2 cytokines, was additive with fluticasone propionate, and inhibited cytokine release from human lung fragments. Finally, we describe an in vivo pharmacodynamic assay that allows rapid preclinical development without animal efficacy models. 相似文献
9.
Kenji Matsuno Kazushige Takai Yoshinobu Isaka Yuka Unno Masayuki Sato Osamu Takikawa Akira Asai 《Bioorganic & medicinal chemistry letters》2010,20(17):5126-5129
S-Benzylisothiourea 3a was discovered by its ability to inhibit indoleamine-2,3-dioxygenase (IDO) in our screening program. Subsequent optimization of the initial hit 3a lead to the identification of sub-μM inhibitors 3r and 10h, both of which suppressed kynurenine production in A431 cells. Synthesis and structure–activity relationship of S-benzylisothiourea analogues as small-molecule inhibitors of IDO are described. 相似文献
10.
Jing Li Tamer S. Kaoud Christophe Laroche Kevin N. Dalby Sean M. Kerwin 《Bioorganic & medicinal chemistry letters》2009,19(22):6293-6297
Based on the mild, thermal rearrangement of 1,2-dialkynylimidazoles to reactive carbene or diradical intermediates, a series of 1,2-dialkynylimidazoles were designed as potential irreversible p38 MAP kinase α-isoform (p38α) inhibitors. The synthesis of these dialkynylimidazoles and their kinase inhibition activity is reported. The 1-ethynyl-substituted dialkynylimidazole 14 is a potent (IC50 = 200 nM) and selective inhibitor of p38α. Moreover, compound 14 covalently modifies p38α as determined by ESI-MS after 12 h incubation at 37 °C. The unique kinase inhibition, covalent kinase adduct formation, and minimal CYP450 2D6 inhibition by compound 14 demonstrate that dialkynylimidazoles are a new, promising class of p38α inhibitors. 相似文献
11.
Targeting the epidermal growth factor receptor kinase (EGFR) with ATP-competitive kinase inhibitors results in dramatic but short-lived responses in patients with EGFR mutant non small cell lung cancer. A series of novel covalent EGFR kinase inhibitors with selectivity for the clinically relevant T790M ‘gatekeeper’ resistance mutation relative to wild-type EGFR were discovered by library screening. A representative compound 3i was obtained through a systematic SAR study guided by mutant EGFR-dependent cellular proliferation assays. 相似文献
12.
《Bioorganic & medicinal chemistry letters》2014,24(24):5836-5839
Identification of inhibitors for protein–protein interactions (PPIs) from high-throughput screening (HTS) is challenging due to the weak affinity of primary hits. We present a hit validation strategy of PPI inhibitors using quantitative ligand displacement assay. From an HTS for Bcl-xL/Mcl-1 inhibitors, we obtained a hit candidate, I1, which potentially forms a reactive Michael acceptor, I2, inhibiting Bcl-xL/Mcl-1 through covalent modification. We confirmed rapid reversible and competitive binding of I1 with a probe peptide, suggesting non-covalent binding. The advantages of our approach over biophysical assays include; simplicity, higher throughput, low protein consumption and universal application to PPIs including insoluble membrane proteins. 相似文献
13.
Federica Vacondio Caterina Carmi Elena Galvani Michele Bassi Claudia Silva Alessio Lodola Silvia Rivara Andrea Cavazzoni Roberta R. Alfieri Pier Giorgio Petronini Marco Mor 《Bioorganic & medicinal chemistry letters》2013,23(19):5290-5294
In the present study, a small set of reversible or irreversible 4-anilinoquinazoline EGFR inhibitors was tested in A549 cells at early (1 h) and late (8 h) time points after inhibitor removal from culture medium. A combination of assays was employed to explain the observed long-lasting inhibition of EGFR autophosphorylation. We found that EGFR inhibition at 8 h can be due, besides to the covalent interaction of the inhibitor with Cys797, as for PD168393 (2) and its prodrug 4, to the intracellular accumulation of non-covalent inhibitors by means of an active cell uptake, as for 5 and 6. Compounds 5–6 showed similar potency and duration of inhibition of EGFR autophosphorylation as the covalent inhibitor 2, while being devoid of reactive groups forming covalent bonds with protein thiols. 相似文献
14.
Hu Y Cole D Denny RA Anderson DR Ipek M Ni Y Wang X Thaisrivongs S Chamberlain T Hall JP Liu J Luong M Lin LL Telliez JB Gopalsamy A 《Bioorganic & medicinal chemistry letters》2011,21(16):4758-4761
Synthesis, modeling and structure-activity relationship of indazoles as inhibitors of Tpl2 kinase are described. From a high throughput screening effort, we identified an indazole hit compound 5 that has a single digit micromolar Tpl2 activity. Through SAR modifications at the C3 and C5 positions of the indazole, we discovered compound 31 with good potency in LANCE assay and cell-based p-Erk assay. 相似文献
15.
Zhiqing Liu Yingmin Zhu Haiying Chen Pingyuan Wang Fang C. Mei Na Ye Xiaodong Cheng Jia Zhou 《Bioorganic & medicinal chemistry letters》2017,27(23):5163-5166
Exchange proteins directly activated by cAMP (EPACs) are critical cAMP-dependent signaling pathway mediators that play important roles in cancer, diabetes, heart failure, inflammations, infections, neurological disorders and other human diseases. EPAC specific modulators are urgently needed to explore EPAC’s physiological function, mechanism of action and therapeutic applications. On the basis of a previously identified EPAC specific inhibitor hit ESI-09, herein we have designed and synthesized a novel series of 2-substituted phenyl-N-phenyl-2-oxoacetohydrazonoyl cyanides as potent EPAC inhibitors. Compound 31 (ZL0524) has been discovered as the most potent EPAC inhibitor with IC50 values of 3.6?µM and 1.2??µM against EPAC1 and EPAC2, respectively. Molecular docking of 31 onto an active EPAC2 structure predicts that 31 occupies the hydrophobic pocket in cAMP binding domain (CBD) and also opens up new space leading to the solvent region. These findings provide inspirations for discovering next generation of EPAC inhibitors. 相似文献
16.
《Bioorganic & medicinal chemistry letters》2014,24(22):5199-5202
A number of cytotoxic conjugated unsaturated ketones were screened for their membrane permeability characteristics using Caco-2 and MDCK cells with the view of finding promising leads for in vivo evaluations. 3b–e and 4a–b demonstrated high permeability characteristics. In particular, 4a emerged as a promising lead which showed excellent apparent permeability (Papp: 54.70) and efflux ratio (ER: 0.15) values. In general, the relative apparent permeabilities of these enones are similar in both bioassays. 相似文献
17.
Venkateshwar Rao Gummadi Sujatha Rajagopalan Chung-Yeng Looi Mohammadjavad Paydar Girish Aggunda Renukappa Bharathi Raja Ainan Narasimha Rao Krishnamurthy Sunil Kumar Panigrahi Kumari Mahasweta Sangeetha Raghuramachandran Manoj Rajappa Anuradha Ramanathan Anirudha Lakshminarasimhan Murali Ramachandra Pooi-Fong Wong Mohammad Rais Mustafa Srinivas Nanduri Subramanya Hosahalli 《Bioorganic & medicinal chemistry letters》2013,23(17):4911-4918
We have identified a novel 7-azaindole series of anaplastic lymphoma kinase (ALK) inhibitors. Compounds 7b, 7m and 7n demonstrate excellent potencies in biochemical and cellular assays. X-ray crystal structure of one of the compounds (7k) revealed a unique binding mode with the benzyl group occupying the back pocket, explaining its potency towards ALK and selectivity over tested kinases particularly Aurora-A. This binding mode is in contrast to that of known ALK inhibitors such as Crizotinib and NVP-TAE684 which occupy the ribose binding pocket, close to DFG motif. 相似文献
18.
《Bioorganic & medicinal chemistry》2020,28(7):115372
Histone-lysine N-methyltransferase SET7 emerged as a potential target for multiple cancers. In a virtual screening program used to explore new and potent inhibitors of SET7, compound 16 was discovered as a top hit with an IC50 value of 6.02 μM. A further similarity search afforded a new compound 23, which exhibited better activity against SET7 with an IC50 value of 1.96 μM. Importantly, compound 23 selectively inhibited the proliferation of MV4-11 cells. Comprehensively, compound 23 can serve as a lead for further identification and development of more potent SET7 inhibitors. 相似文献
19.
Tanja Schirmeister Janina Schmitz Sascha Jung Torsten Schmenger R. Luise Krauth-Siegel Michael Gütschow 《Bioorganic & medicinal chemistry letters》2017,27(1):45-50
A series of dipeptide nitriles known as inhibitors of mammalian cathepsins were evaluated for inhibition of rhodesain, the cathepsin L-like protease of Trypanosoma brucei. Compound 35 consisting of a Leu residue fitting into the S2 pocket and a triarylic moiety consisting of thiophene, a 1,2,4-oxadiazole and a phenyl ring fitting into the S3 pocket, and compound 33 with a 3-bromo-Phe residue (S2) and a biphenyl fragment (S3) were found to inhibit rhodesain in the single-digit nanomolar range. The observed steep structure-activity relationship could be explained by covalent docking simulations. With their high selectivity indices (ca. 200) and the good antitrypanosomal activity (8 μM) the compounds represent promising starting points for new rhodesain inhibitors. 相似文献
20.
Lakshmaiah Gingipalli Michael H. Block Larry Bao Emma Cooke Les A. Dakin Christopher R. Denz Andrew D. Ferguson Jeffrey W. Johannes Nicholas A. Larsen Paul D. Lyne Timothy W. Pontz Tao Wang Xiaoyun Wu Allan Wu Hai-Jun Zhang Xiaolan Zheng James E. Dowling Michelle L. Lamb 《Bioorganic & medicinal chemistry letters》2018,28(8):1336-1341
The design and synthesis of a novel series of 2,6-disubstituted pyrazine derivatives as CK2 kinase inhibitors is described. Structure-guided optimization of a 5-substituted-3-thiophene carboxylic acid screening hit (3a) led to the development of a lead compound (12b), which shows inhibition in both enzymatic and cellular assays. Subsequent design and hybridization efforts also led to the unexpected identification of analogs with potent PIM kinase activity (14f). 相似文献