共查询到20条相似文献,搜索用时 78 毫秒
1.
Hong Lin Dennis S. Yamashita Jin Zeng Ren Xie Sharad Verma Juan I. Luengo Nelson Rhodes Shuyun Zhang Kimberly A. Robell Anthony E. Choudhry Zhihong Lai Rakesh Kumar Elisabeth A. Minthorn Kristin K. Brown Dirk A. Heerding 《Bioorganic & medicinal chemistry letters》2010,20(2):679-683
A novel series of AKT inhibitors containing 2,3,5-trisubstituted pyridines with novel azaindazoles as hinge binding elements are described. Among these, the 4,7-diazaindazole compound 2c has improved drug-like properties and kinase selectivity than those of indazole 1, and displays greater than 80% inhibition of GSK3β phosphorylation in a BT474 tumor xenograft model in mice. 相似文献
2.
Saravanan Parthasarathy Kenneth Henry Huaxing Pei Josh Clayton Mark Rempala Deidre Johns Oscar De Frutos Pablo Garcia Carlos Mateos Sehila Pleite Yong Wang Stephanie Stout Bradley Condon Sheela Ashok Zhohai Lu William Ehlhardt Tom Raub Mei Lai Timothy P. Burkholder 《Bioorganic & medicinal chemistry letters》2018,28(10):1887-1891
During the course of our research efforts to develop potent and selective AKT inhibitors, we discovered enatiomerically pure substituted dihydropyridopyrimidinones (DHP) as potent inhibitors of protein kinase B/AKT with excellent selectivity against ROCK2. A key challenge in this program was the poor physicochemical properties of the initial lead compound 5. Integration of structure-based drug design and physical properties-based design resulted in replacement of a highly hydrophobic poly fluorinated aryl ring by a simple trifluoromethyl that led to identification of compound 6 with much improved physicochemical properties. Subsequent SAR studies led to the synthesis of new pyran analog 7 with improved cell potency. Further optimization of pharmacokintetics properties by increasing permeability with appropriate fluorinated alkyl led to compound 8 as a potent, selective AKT inhibitors that blocks the phosphorylation of GSK3β in vivo and had robust, dose and concentration dependent efficacy in the U87MG tumor xenograft model. 相似文献
3.
《Bioorganic & medicinal chemistry》2016,24(5):957-966
The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is related to cellular activities. Abnormalities of this signaling pathway were discovered in various cancers, including hepatocellular carcinoma (HCC). The PI3K/mTOR dual inhibitors were proposed to have enhanced antitumor efficacies by targeting multiple points of the signaling pathway. We synthesized a series of propynyl-substituted benzenesulfonamide derivatives as PI3K/mTOR dual inhibitors. Compound 7k (NSC781406) was identified as a highly potent dual inhibitor, which exhibited potent tumor growth inhibition in the hepatocellular carcinoma BEL-7404 xenograft model. Compound 7k may be a potential therapeutic drug candidate for HCC. 相似文献
4.
《Bioorganic & medicinal chemistry》2014,22(1):366-373
Herein, we describe the discovery and synthesis of a new series of 1,2,4,7-tetra-substituted indole derivatives as novel AKT inhibitors by optimization of a weak hit methyl 4-(2-aminoethoxy)-1H-indole-2-carboxylate (1). Both representative compounds 6a and 6o exhibited the most potent inhibitory activities against AKT1, with inhibition rates of 72.5% and 78.6%, respectively, at concentrations of 10 nM. In addition, compounds 6a and 6o also potently inhibited the phosphorylation of the downstream GSK3 protein and displayed slightly better anti-proliferative activities in a prostate cancer cell line. 相似文献
5.
Qingping Zeng Matthew P. Bourbeau G. Erich Wohlhieter Guomin Yao Holger Monenschein James T. Rider Matthew R. Lee Shiwen Zhang Julie Lofgren Daniel Freeman Chun Li Elizabeth Tominey Xin Huang Douglas Hoffman Harvey Yamane Andrew S. Tasker Celia Dominguez Vellarkad N. Viswanadhan Randall Hungate Xiaoling Zhang 《Bioorganic & medicinal chemistry letters》2010,20(5):1652-1656
A series of 2-aminothiadiazole of inhibitors of AKT1 is described. SAR relationships are discussed, along with selectivity for protein kinase A (PKA) and cyclin-dependent kinase 2 (CDK2). Moderate selectivity observed in several compounds for AKT1 versus PKA is rationalized by X-ray crystallographic analysis. Key compounds showed activity in cellular assays measuring phosphorylation of two AKT substrates, PRAS40 and FKHRL1. Compound 30 was advanced to a mouse liver PD assay, where it showed dose-dependent inhibition of AKT activity, as measured by the inhibition of phospho-PRAS40. 相似文献
6.
Mark A. Seefeld Meagan B. Rouse Kenneth C. McNulty Lihui Sun Jizhou Wang Dennis S. Yamashita Juan I. Luengo ShuYun Zhang Elisabeth A. Minthorn Nestor O. Concha Dirk A. Heerding 《Bioorganic & medicinal chemistry letters》2009,19(8):2244-2248
A pyrrolopyridinyl thiophene carboxamide 7 was discovered as a tractable starting point for a lead optimization effort in an AKT kinase inhibition program. SAR studies aided by a co-crystal structure of 7 in AKT2 led to the identification of AKT inhibitors with subnanomolar potency. Representative compounds showed antiproliferative activity as well as inhibition of phosphorylation of the downstream target GSK3β. 相似文献
7.
Supriya Gaitonde Surya K De Marianna Tcherpakov Antimone Dewing Hongbin Yuan Megan Riel‐Mehan Stan Krajewski Gavin Robertson Maurizio Pellecchia Ze’ev Ronai 《Pigment cell & melanoma research》2009,22(2):187-195
The AKT/PKB pathway plays a central role in tumor development and progression and is often up‐regulated in different tumor types, including melanomas. We have recently reported on the in silico approach to identify putative inhibitors for AKT/PKB. Of the reported hits, we selected BI‐69A11, a compound which was shown to inhibit AKT activity in in vitro kinase assays. Analysis of BI‐69A11 was performed in melanoma cells, a tumor type that commonly exhibits up‐regulation of AKT. Treatment of the UACC903 human melanoma cells, harboring the PTEN mutation, with BI‐69A11 caused efficient inhibition of AKT S473 phosphorylation with concomitant inhibition of AKT phosphorylation of PRAS40. Treatment of melanoma cells with BI‐69A11 also reduced AKT protein expression, which coincided with inhibition of AKT association with HSP‐90. BI‐69A11 treatment not only caused cell death of melanoma, but also prostate tumor cell lines. Notably, the effect of BI‐69A11 on cell death was more pronounced in cells that express an active form of AKT. Significantly, intra‐peritoneal injection of BI‐69A11 caused effective regression of melanoma tumor xenografts, which coincided with elevated levels of cell death. These findings identify BI‐69A11 as a potent inhibitor of AKT that is capable of eliciting effective regression of xenograft melanoma tumors. 相似文献
8.
Yi Yu Ronald E. Savage Sudharshan Eathiraj Justin Meade Michael J. Wick Terence Hall Giovanni Abbadessa Brian Schwartz 《PloS one》2015,10(10)
As a critical component in the PI3K/AKT/mTOR pathway, AKT has become an attractive target for therapeutic intervention. ARQ 092 and a next generation AKT inhibitor, ARQ 751 are selective, allosteric, pan-AKT and AKT1-E17K mutant inhibitors that potently inhibit phosphorylation of AKT. Biochemical and cellular analysis showed that ARQ 092 and ARQ 751 inhibited AKT activation not only by dephosphorylating the membrane-associated active form, but also by preventing the inactive form from localizing into plasma membrane. In endometrial PDX models harboring mutant AKT1-E17K and other tumor models with an activated AKT pathway, both compounds exhibited strong anti-tumor activity. Combination studies conducted in in vivo breast tumor models demonstrated that ARQ 092 enhanced tumor inhibition of a common chemotherapeutic agent (paclitaxel). In a large panel of diverse cancer cell lines, ARQ 092 and ARQ 751 inhibited proliferation across multiple tumor types but were most potent in leukemia, breast, endometrial, and colorectal cancer cell lines. Moreover, inhibition by ARQ 092 and ARQ 751 was more prevalent in cancer cell lines containing PIK3CA/PIK3R1 mutations compared to those with wt-PIK3CA/PIK3R1 or PTEN mutations. For both ARQ 092 and ARQ 751, PIK3CA/PIK3R1 and AKT1-E17K mutations can potentially be used as predictive biomarkers for patient selection in clinical studies. 相似文献
9.
Joel T. Arcari Jean S. Beebe Martin A. Berliner Vincent Bernardo Merin Boehm Gary V. Borzillo Tracey Clark Bruce D. Cohen Richard D. Connell Heather N. Frost Deborah A. Gordon William M. Hungerford Shefali M. Kakar Aaron Kanter Nandell F. Keene Elizabeth A. Knauth Susan D. LaGreca Yong Lu Jinshan M. Chen 《Bioorganic & medicinal chemistry letters》2013,23(10):3059-3063
The synthesis and biological evaluation of novel Tie-2 kinase inhibitors are presented. Based on the pyrrolopyrimidine chemotype, several new series are described, including the benzimidazole series by linking a benzimidazole to the C5-position of the 4-amino-pyrrolopyrimidine core and the ketophenyl series synthesized by incorporating a ketophenyl group to the C5-position. Medicinal chemistry efforts led to potent Tie-2 inhibitors. Compound 15, a ketophenyl pyrrolopyrimidine urea analog with improved physicochemical properties, demonstrated favorable in vitro attributes as well as dose responsive and robust oral tumor growth inhibition in animal models. 相似文献
10.
Ho Shin Kim Van-Hai Hoang Mannkyu Hong Kyung Chul Kim Jihyae Ann Cong-Truong Nguyen Ji Hae Seo Hoon Choi Jun Yong Kim Kyu-Won Kim Woong Sub Byun Sangkook Lee Seungbeom Lee Young-Ger Suh Jie Chen Hyun-Ju Park Tae-Min Cho Ji Young Kim Jeewoo Lee 《Bioorganic & medicinal chemistry》2019,27(7):1370-1381
On the basis of deguelin, a series of the B,C-ring truncated surrogates with N-substituted amide linkers were investigated as HSP90 inhibitors. The structure activity relationship of the template was studied by incorporating various substitutions on the nitrogen of the amide linker and examining their HIF-1α inhibition. Among them, compound 57 showed potent HIF-1α inhibition and cytotoxicity in triple-negative breast cancer lines in a dose-dependent manner. Compound 57 downregulated expression and phosphorylation of major client proteins of HSP90 including AKT, ERK and STAT3, indicating that its antitumor activity was derived from the inhibition of HSP90 function. The molecular modeling of 57 demonstrated that 57 bound well to the C-terminal ATP-binding pocket in the open conformation of the hHSP90 homodimer with hydrogen bonding and pi-cation interactions. Overall, compound 57 is a potential antitumor agent for triple-negative breast cancer as a HSP90 C-terminal inhibitor. 相似文献
11.
《Bioorganic & medicinal chemistry letters》2014,24(6):1597-1599
In an effort to discover potent antitumor agents, a series of novel C-7-heteroaryl-substituted camptothecin derivatives were designed and synthesized via microwave-promoted Suzuki coupling reaction. These analogs were then assessed for cytotoxicity against three human tumor cell lines, A549, HCT116, HT-29, and inhibitory effects on topoisomerase I. All of the new compounds showed potent inhibition of human tumor cell growth, among which compound 10a showed higher cytotoxic activity than that of SN-38. Furthermore, this series of compounds retained or enhanced Topo I inhibition. 相似文献
12.
Alessandro A. Boezio Loren Berry Brian K. Albrecht David Bauer Steven F. Bellon Christiane Bode April Chen Deborah Choquette Isabelle Dussault Satoko Hirai Paula Kaplan-Lefko Jay F. Larrow Min-Hwa Jasmine Lin Julia Lohman Michele H. Potashman Karen Rex Michael Santostefano Kavita Shah Roman Shimanovich Stephanie K. Springer Yohannes Teffera Yajing Yang Yihong Zhang Jean-Christophe Harmange 《Bioorganic & medicinal chemistry letters》2009,19(22):6307-6312
Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. We previously showed that O-linked triazolopyridazines can be potent inhibitors of c-Met. Herein, we report the discovery of a related series of N-linked triazolopyridazines which demonstrate nanomolar inhibition of c-Met kinase activity and display improved pharmacodynamic profiles. Specifically, the potent time-dependent inhibition of cytochrome P450 associated with the O-linked triazolopyridazines has been eliminated within this novel series of inhibitors. N-linked triazolopyridazine 24 exhibited favorable pharmacokinetics and displayed potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver PD model. Once-daily oral administration of 24 for 22 days showed significant tumor growth inhibition in an NIH-3T3/TPR-Met xenograft mouse efficacy model. 相似文献
13.
Michael P. Trova Keith D. Barnes Curt Barford Travis Benanti Mark Bielaska Lori Burry John M. Lehman Christine Murphy Harold O’Grady Denise Peace Susan Salamone Jennifer Smith Patricia Snider Joseph Toporowski Steven Tregay Alison Wilson Michael Wyle Xiaozhang Zheng Thomas D. Friedrich 《Bioorganic & medicinal chemistry letters》2009,19(23):6608-6612
The introduction of an aryl ring onto the 4-position of the C-6 benzyl amino group of the Cdk inhibitor roscovitine (2), maintained the potent Cdk inhibition demonstrated by roscovitine (2) as well as greatly improving the antiproliferative activity. A series of C-6 biarylmethylamino derivatives was prepared addressing modifications on the C-6 biaryl rings, N-9 and C-2 positions to provide compounds that displayed potent cytotoxic activity against tumor cell lines. In particular, derivative 21h demonstrated a >750-fold improvement in the growth inhibition of HeLa cells compared to roscovitine (2). 相似文献
14.
Lin X Murray JM Rico AC Wang MX Chu DT Zhou Y Del Rosario M Kaufman S Ma S Fang E Crawford K Jefferson AB 《Bioorganic & medicinal chemistry letters》2006,16(16):4163-4168
A series of 2-pyrimidyl-5-amidothiophenes has been synthesized and evaluated for AKT inhibition. SAR studies resulted in potent inhibitors of AKT with IC(50) values as low as single digit nanomolar as represented by compound 2aa. Compound 2aa showed cellular activity including antiproliferation and downstream target modulation. Selectivity profile is described. A co-crystal of 2aa with PKA is determined and discussed. 相似文献
15.
Kuen-Feng Chen Kuan-Chuan Pao Jung-Chen Su Yi-Chieh Chou Chun-Yu Liu Hui-Ju Chen Jui-Wen Huang InKi Kim Chung-Wai Shiau 《Bioorganic & medicinal chemistry》2012,20(20):6144-6153
Cancerous inhibitor of PP2A (CIP2A) is a novel human oncoprotein that inhibits PP2A, contributing to tumor aggressiveness in various cancers. Several studies have shown that downregulation of CIP2A by small molecules reduces PP2A-dependent phosphorylation of Akt and induces cell death. Here, a series of mono- and di-substituted quinazoline and pyrimidine derivatives based on the skeleton of erlotinib (an EGFR inhibitor) were synthesized and their bioactivities against hepatocellular carcinoma were evaluated. The di-substituted quinazoline and pyrimidine derivatives were more potent inhibitors of cancer-cell proliferation than the mono-substituted derivatives. In particular, compound 1 with chloride at position 2 of quinazoline was as potent as erlotinib in inducing cell death but no inhibition for EGFR activity. Further assays confirmed a correlation between cell death, and CIP2A and Akt inhibition by these derivatives. Among all the derivatives, compounds 19 and 22 showed the most potent antiproliferative activities and the strongest inhibition of CIP2A and p-Akt expression. 相似文献
16.
Hong Lin Dennis S. Yamashita Jin Zeng Ren Xie Wenyong Wang Sirishkumar Nidarmarthy Juan I. Luengo Nelson Rhodes Victoria B. Knick Anthony E. Choudhry Zhihong Lai Elisabeth A. Minthorn Susan L. Strum Edgar R. Wood Patricia A. Elkins Nestor O. Concha Dirk A. Heerding 《Bioorganic & medicinal chemistry letters》2010,20(2):673-678
2,3,5-Trisubstituted pyridines have been designed as potent AKT inhibitors that are selective against ROCK1 based on the comparison between AKT and ROCK1 structures. Substitution at the 2-position of the core pyridine is the key element to provide selectivity against ROCK1. An X-ray co-crystal structure of 9p in PKA supports the proposed rationale of ROCK1 selectivity. 相似文献
17.
Alexander L. Ruchelman Hon-Wah Man Weihong Zhang Roger Chen Lori Capone Jian Kang Anastasia Parton Laura Corral Peter H. Schafer Darius Babusis Mehran F. Moghaddam Yang Tang Michael A. Shirley George W. Muller 《Bioorganic & medicinal chemistry letters》2013,23(1):360-365
A series of analogs of the immunomodulary drugs lenalidomide (1) and pomalidomide (2), in which the amino group is replaced with various isosteres, was prepared and assayed for immunomodulatory activity and activity against cancer cell lines. The 4-methyl and 4-chloro analogs 4 and 15, respectively, displayed potent inhibition of tumor necrosis factor-α (TNF-α) in LPS-stimulated hPBMC, potent stimulation of IL-2 in a human T cell co-stimulation assay, and anti-proliferative activity against the Namalwa lymphoma cell line. Both of these analogs displayed oral bioavailability in rat. 相似文献
18.
Design,synthesis, and biological evaluation of some novel 4-aminoquinazolines as Pan-PI3K inhibitors
Huai-Wei Ding Shu Wang Xiao-Chun Qin Jian Wang Hong-Rui Song Qing-Chun Zhao Shao-Jiang Song 《Bioorganic & medicinal chemistry》2019,27(13):2729-2740
A series of 4-aminoquinazolines derivatives containing hydrophilic group were designed and identified as potent Pan-PI3K inhibitors in this study. The results of antiproliferative assays in vitro showed that this series of compounds had strong inhibition of tumor growth, especially compound 7b for MCF-7 cells but weak inhibition to normal cells. PI3K kinase assay showed that 7b had high activity for three PI3K isoforms with the IC50 values of picomole. The western blot assay indicated that 7b could decrease the phospho-Akt (S473) in a dose-dependent manner. Further experiments showed that 7b could induce apoptosis in MCF-7 cells. Four key hydrogen bonding interactions were found in the docking of 7b with PI3K kinase. All these results suggested that 7b is a potent PI3K inhibitor and could be considered as a potential candidate for the development of anticancer agents. 相似文献
19.
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
20.
《Bioorganic & medicinal chemistry》2014,22(14):3739-3748
The fragment of 2-substituted-3-sulfonylaminobenzamide has been proposed to replace the fragment of 2-substituted-3-sulfonylaminopyridine in PI3K and mTOR dual inhibitors to design novel anticancer agents based on bioisostere. The combination of the fragment of 2-substituted-3-sulfonylaminobenzamide with the fragment of 2-aminobenzothiazole or 2-aminothiazolo[5,4-b]pyridine, or 2-amino[1,2,4]triazolo[1,5-a]pyridine produced the novel structures of anticancer agents. As a result, nineteen target compounds were synthesized and characterized. Their antiproliferative activities in vitro were evaluated via MTT assay against four human cancer cell lines including HCT-116, A549, MCF-7 and U-87 MG. The SAR of target compounds was preliminarily discussed. Compound 1g with potent antiproliferative activity was examined for its effect on the AKT and p-AKT473. The anticancer effect of 1g was evaluated in established nude mice HCT-116 xenograft model. The results suggested that compound 1g can block PI3K/AKT/mTOR pathway and significantly inhibit tumor growth. These findings strongly support our assumption that the fragment of benzamide can replace the pyridine ring in some PI3K and mTOR dual inhibitor to design novel anticancer agents. 相似文献