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ABSTRACT: Structure-guided design led to the discovery of novel chemical scaffolds for B-Raf inhibitors. Both type I and type II kinase inhibitors have been explored and lead compounds with good potency and excellent selectivity have been identified.
Bioorganic & medicinal chemistry letters 12/2011; 21(23):6941-4. · 2.65 Impact Factor
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Xiaolun Wang,
Dan M Berger,
Edward J Salaski,
Nancy Torres,
Minu Dutia,
Cilien Hanna,
Yongbo Hu,
Jeremy I Levin, Dennis Powell,
Donald Wojciechowicz,
Karen Collins,
Eileen Frommer,
Judy Lucas
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ABSTRACT: Novel indazolylpyrazolo[1,5-a]pyrimidine analogues have been prepared and found to be extremely potent type I B-Raf inhibitors. The lead compound shows good selectivity against a panel of 60 kinases, possesses a desirable pharmacokinetic profile, and demonstrates excellent in vivo antitumor efficacy in B-Raf mutant xenograft models.
Journal of Medicinal Chemistry 10/2010; 53(21):7874-8. · 4.80 Impact Factor
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Dan M Berger,
Nancy Torres,
Minu Dutia, Dennis Powell,
Greg Ciszewski,
Ariamala Gopalsamy,
Jeremy I Levin,
Kyung-Hee Kim,
Weixin Xu,
James Wilhelm,
YongBo Hu,
Karen Collins,
Larry Feldberg,
Steven Kim,
Eileen Frommer,
Donald Wojciechowicz,
Robert Mallon
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ABSTRACT: As part of our research effort to discover B-Raf kinase inhibitors, we prepared a series of C-3 substituted N-(3-(pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-3-(trifluoromethyl)benzamides. X-ray crystallography studies revealed that one of the more potent inhibitors (10n) bound to B-Raf kinase without forming a hinge-binding hydrogen bond. With basic amine residues appended to C-3 aryl residues, cellular activity and solubility were enhanced over previously described compounds of this class.
Bioorganic & medicinal chemistry letters 12/2009; 19(23):6519-23. · 2.65 Impact Factor
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ABSTRACT: A series of pyrazolo[1,5-alpha]pyrimidine analogs has been prepared and found to be potent and selective B-Raf inhibitors. Molecular modeling suggests they bind to the active conformation of the enzyme.
Bioorganic & medicinal chemistry letters 12/2009; 19(23):6571-4. · 2.65 Impact Factor
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ABSTRACT: It was found that solvent hydrogen bond basicity (SHBB) significantly affects the regiochemistry of the S(N)Ar reaction between secondary amines and activated polyfluoroarenes. A plausible mechanism involving a six-membered transition state is invoked for the formation of an ortho-substituted isomer, which is likely organized by a hydrogen bond. Evidence for this hypothesis is presented, and a regioselective amination reaction of activated polyfluoroarenes has been developed.
Organic Letters 11/2009; 11(24):5662-4. · 5.86 Impact Factor
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Martin J Di Grandi,
Dan M Berger,
Darrin W Hopper,
Chunchun Zhang,
Minu Dutia,
Alejandro L Dunnick,
Nancy Torres,
Jeremy I Levin,
George Diamantidis,
Christoph W Zapf,
Jonathan D Bloom,
YongBo Hu, Dennis Powell,
Donald Wojciechowicz,
Karen Collins,
Eileen Frommer
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ABSTRACT: A novel series of pyrazolo[1,5-a]pyrimidines bearing a 3-hydroxyphenyl group at C(3) and substituted tropanes at C(7) have been identified as potent B-Raf inhibitors. Exploration of alternative functional groups as a replacement for the C(3) phenol demonstrated indazole to be an effective isostere. Several compounds possessing substituted indazole residues, such as 4e, 4p, and 4r, potently inhibited cell proliferation at submicromolar concentrations in the A375 and WM266 cell lines, and the latter two compounds also exhibited good therapeutic indices in cells.
Bioorganic & medicinal chemistry letters 10/2009; 19(24):6957-61. · 2.65 Impact Factor
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Edward J Salaski,
Girija Krishnamurthy,
Wei-Dong Ding,
Ker Yu,
Shabana S Insaf,
Clark Eid,
Jaechul Shim,
Jeremy I Levin,
Keiko Tabei,
Lourdes Toral-Barza,
Wei-Guo Zhang,
Leonard A McDonald,
Erick Honores,
Cilien Hanna,
Ayako Yamashita,
Bernard Johnson,
Zhong Li,
Leif Laakso, Dennis Powell,
Tarek S Mansour
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ABSTRACT: The naturally occurring pyranonaphthoquinone (PNQ) antibiotic lactoquinomycin and related aglycones were found to be selective inhibitors of the serine-threonine kinase AKT. A set of synthetic PNQs were prepared and a minimum active feature set and preliminary SAR were determined. PNQ lactones inhibit the proliferation of human tumor cell lines containing constitutively activated AKT and show expected effects on cellular biomarkers. Biochemical data are presented supporting a proposed bioreductive alkylation mechanism of action.
Journal of Medicinal Chemistry 04/2009; 52(8):2181-4. · 4.80 Impact Factor
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Yanong D Wang,
Erick Honores,
Biqi Wu,
Steve Johnson, Dennis Powell,
Miriam Miranda,
John P McGinnis,
Carolyn Discafani,
Sridhar K Rabindran,
Wendy Cheng,
Girija Krishnamurthy
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ABSTRACT: Checkpoint deficiency of malignant cells can be exploited in cancer drug discovery. Compounds that selectively kill checkpoint-deficient cells versus checkpoint-proficient cells can be utilized to preferentially target tumor cells, while sparing normal cells. The protein p21(Wafl/Cipl/Sdi1) (hereafter referred to as p21) inhibits progression of the cell cycle by inhibiting the activity of G1 kinases (cyclin D/cdk4 and cyclin E-cdk2) and the G2 kinase (cyclin B/cdkl) in response to DNA damage or abnormal DNA content. The expression of p21 is often low in human cancer cells due to frequent loss of the upstream activator, p53, and is associated with poor prognosis in some cancer patients. Using an isogenic pair of cell lines, HCT116 (p21+/+) and 80S14 (p21-/-), we have disclosed previously a novel series of pyrazolo[1,5-a]pyrimidines that preferentially kill the p21-deficient cells. We will present the synthesis, biological activities and SAR study of a series of pyrazolo[1,5-a]pyrimidines with an optimized phenyl amide moiety at the C-7 position. The mechanism of action of these compounds will also be discussed.
Bioorganic & medicinal chemistry 01/2009; 17(5):2091-100. · 2.82 Impact Factor
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Yixian Zhang,
Maria Gavriil,
Judy Lucas,
Sreekala Mandiyan,
Max Follettie,
Veronica Diesl,
Fuk-Wah Sum, Dennis Powell,
Steve Haney,
Robert Abraham,
Kim Arndt
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ABSTRACT: Tumor necrosis factor alpha (TNFalpha) has been used to treat patients with certain tumor types. However, its antitumor activity has been undermined by the activation of IkappaBalpha kinase (IKK), which in turn activates nuclear factor-kappaB (NF-kappaB) to help cancer cells survive. Therefore, inhibition of TNFalpha-induced IKK activity with specific IKK inhibitor represents an attractive strategy to treat cancer patients. This study reveals IKI-1 as a potent small molecule inhibitor of IKKalpha and IKKbeta, which effectively blocked TNFalpha-mediated IKK activation and subsequent NF-kappaB activity. Using gene profiling analysis, we show that IKI-1 blocked most of the TNFalpha-mediated mRNA expression, including many genes that play important roles in cell survival. We further show that in vitro and in vivo combination of TNFalpha with IKI-1 had superior potency than either agent alone. This increased potency was due primarily to the increased apoptosis in the presence of both TNFalpha and IKI-1. Additionally, IKKbeta small interfering RNA transfected cells were more sensitive to the treatment of TNFalpha. The study suggests that the limited efficacy of TNFalpha in cancer treatment was due in part to the activation of NF-kappaB, allowing tumor cells to escape apoptosis. Therefore, the combination of IKI-1 with TNFalpha may improve the efficacy of TNFalpha for certain tumor types.
Cancer Research 12/2008; 68(22):9519-24. · 7.86 Impact Factor
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Dan M Berger,
Minu Dutia, Dennis Powell,
Middleton B Floyd,
Nancy Torres,
Robert Mallon,
Donald Wojciechowicz,
Steven Kim,
Larry Feldberg,
Karen Collins,
Inder Chaudhary
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ABSTRACT: A series of substituted 7-alkenyl 4[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)]anilino-3-quinolinecarbonitrile analogs were synthesized and evaluated as MEK1 kinase inhibitors. The synthetic details, structure-activity relationships, biological activity, and selected oral exposure studies of these analogs are described. From these studies, compound 5m was chosen as a strong candidate for further evaluation. The selectivity of 5m was ascertained against a panel of 17 kinases, where activity was observed against EGFR, Src, Lyn, and IR kinases. Western blot studies in WM-266 cells demonstrated that 5m inhibited phosphorylation of ERK, while additional kinase pathways tested showed no inhibition at up to 10 microM of 5 m. PK studies, as well as a xenograft and in vivo biomarker studies are described for 5m.
Bioorganic & medicinal chemistry 10/2008; 16(20):9202-11. · 2.82 Impact Factor
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Neelu Kaila,
Neal Green,
Huan-Qiu Li,
Yonghan Hu,
Kristin Janz,
Lori Krim Gavrin,
Jennifer Thomason,
Steve Tam, Dennis Powell,
John Cuozzo,
J Perry Hall,
Jean-Baptiste Telliez,
Sang Hsu,
Cheryl Nickerson-Nutter,
Qin Wang,
Lih-Ling Lin
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ABSTRACT: We have previously reported the discovery and initial SAR of the [1,7]naphthyridine-3-carbonitriles and quinoline-3-carbonitriles as Tumor Progression Loci-2 (Tpl2) kinase inhibitors. In this paper, we report new SAR efforts which have led to the identification of 4-alkylamino-[1,7]naphthyridine-3-carbonitriles. These compounds show good in vitro and in vivo activity against Tpl2 and improved pharmacokinetic properties. In addition they are highly selective for Tpl2 kinase over other kinases, for example, EGFR, MEK, MK2, and p38. Lead compound 4-cycloheptylamino-6-[(pyridin-3-ylmethyl)-amino]-[1,7]naphthyridine-3-carbonitrile (30) was efficacious in a rat model of LPS-induced TNF-alpha production.
Bioorganic & Medicinal Chemistry 11/2007; 15(19):6425-42. · 2.92 Impact Factor
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ABSTRACT: A novel series of antiproliferative agents containing pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides, selective for p21-deficient cells, were identified by high-throughput screening. Exploration of the SAR relationships in the headpiece, core, and tailpiece is described. Strict steric, positional, and electronic requirements were observed, with a clear preference for both core nitrogens, a thienoyl headpiece, and meta substituted tailpiece.
Bioorganic & Medicinal Chemistry Letters 04/2007; 17(6):1641-5. · 2.55 Impact Factor
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Dan M Berger,
Minu Dutia,
Gary Birnberg, Dennis Powell,
Diane H Boschelli,
Yanong D Wang,
Malini Ravi,
Deanna Yaczko,
Jennifer Golas,
Judy Lucas,
Frank Boschelli
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ABSTRACT: It has been previously reported that appropriately substituted 4-anilinoquinoline-3-carbonitriles are potent inhibitors of Src kinase, with biological activity in vitro and in vivo. Structural modifications to these compounds have been explored, providing the 4-anilinobenzo[g]quinoline-3-carbonitriles as a series with enhanced Src inhibitory properties. The synthesis and structure-activity relationships of these 4-anilino-7,8-dialkoxybenzo[g]quinoline-3-carbonitriles are presented here. Analogues with cyclic basic amine groups attached via ethoxy linkages at the C-8 position were the most active in vitro, with subnanomolar IC50 values against Src kinase observed for a majority of the compounds synthesized. Compound 17d was more potent in vitro than the analogously substituted 4-anilinoquinoline-3-carbonitrile SKI-606, which is undergoing evaluation in clinical trials. The most potent analogue synthesized was 17a, with an IC50 of 0.15 nM against Src kinase and with an IC50 of 10 nM against Src-transformed fibroblasts. Molecular modeling studies provided a rationale for the exceptional activity observed for these compounds, with favorable van der Waals interactions playing the major role. Compound 17c was found to be highly selective for Src kinase when tested against a panel of other kinases, with modest selectivity versus the Src family kinases Lyn and Fyn. Following ip dosing at 50 mg/kg, analogues 17c and 17d were shown to have plasma levels that significantly exceeded the cellular IC50 values against Src-transformed fibroblasts. In an Src-transformed fibroblast xenograft model, both compounds exhibited a significant inhibition of tumor growth.
Journal of Medicinal Chemistry 10/2005; 48(19):5909-20. · 5.25 Impact Factor
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ABSTRACT: On the basis of a screening lead from an assay using a pair of p21 isogenic cell lines (p21-proficient cells and p21-deficient cells) to identify chemoselective agents, a series of novel thieno[2,3-d]pyrimidin-4(1H)-one-based analogs was prepared. Some analogs inhibited the growth of human colon tumor cells.
Bioorganic & Medicinal Chemistry Letters 09/2005; 15(16):3763-6. · 2.55 Impact Factor
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ABSTRACT: A novel series of p21 chemoselective agents containing a pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides were identified by high throughput screening. Optimization of the amide region by parallel synthesis and the iterative design toward understanding structure-activity relationship to improve potency are described. The isopropyl carbamate derivative 34 was identified as a highly chemoselective agent displaying a potency of 51 nM in the p21 deficient cell line.
Bioorganic & Medicinal Chemistry Letters 04/2005; 15(6):1591-4. · 2.55 Impact Factor
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Robert Mallon,
Larry Feldberg,
Steven Kim,
Karen Collins,
Donald Wojciechowicz,
Constance Kohler,
Diana Kovacs,
Carolyn Discafani,
Nan Zhang,
Biqi Wu,
Brawner Floyd, Dennis Powell,
Dan Berger
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ABSTRACT: A high-throughput screen for Ras-mitogen-activated protein kinase (MAPK) signaling inhibitors identified two series (class 1 and 2) of substituted 4-anilino-3-quinolinecarbonitriles as potent (IC(50)s <10 nmol/L) mitogen-activated protein/extracellular signal-regulated kinase 1 (MEK1) kinase inhibitors. These compounds had cyanoquinoline cores, but differed in their respective aniline groups [1a, 1b: 4-phenoxyphenylaniline; 2a, 2b: 3-chloro-4-(1-methylimidazol-2-sulfanyl)aniline]. These compounds were competitive inhibitors of ATP binding by MEK1 kinase, and they had minimal or no effect on Raf, epidermal growth factor receptor (EGFR), Akt, cyclin-dependent kinase 4 (CDK4), or MK2 kinases at concentrations >100-fold higher than those that inhibited MEK1 kinase. Both class 1 and 2 compounds inhibited in vitro growth of human tumor cell lines. A class 2 compound (2b) was the most potent inhibitor of human tumor cell growth in vitro, and this effect was linked to distinct suppression of MAPK phosphorylation in cells. Compound 2b did not affect phosphorylation status of other kinases, such as EGFR, Akt, and stress-activated protein (SAP)/c-jun-NH kinase (Jnk); nor did it affect overall tyrosine phosphorylation level in cells. However, compound 2b did inhibit MEK1 phosphorylation in cells. Inhibition of MEK1 phosphorylation by 2b was not due to a major effect on Raf kinase activity, because enzyme assays showed minimal Raf kinase inhibition. We believe compound 2b inhibits kinase activity upstream of Raf, and thereby affects MEK1 phosphorylation in cells. Even with the dual effect of 2b on MEK and MAPK phosphorylation, this compound was well tolerated and significantly inhibited growth of the human colon tumor cell line LoVo (at 50 and 100 mg/kg BID, i.p.) in a nude mouse xenograft model.
Molecular Cancer Therapeutics 06/2004; 3(6):755-62. · 5.23 Impact Factor
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ABSTRACT: Several 7-alkoxy-4-anilino-3-quinolinecarbonitriles were synthesized and evaluated for Src kinase inhibitory activity. Optimal inhibition of both Src enzymatic and cellular activity was seen with analogues having a 2,4-dichloro-5-methoxyaniline group at C-4. Compound 18, which has a 1-methylpiperidinemethoxy group at C-7, showed in vivo activity in a xenograft model.
Bioorganic & Medicinal Chemistry Letters 12/2003; 13(21):3797-800. · 2.55 Impact Factor
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Dan Berger,
Minu Dutia, Dennis Powell,
Biqi Wu,
Allan Wissner,
Diane H Boschelli,
M Brawner Floyd,
Nan Zhang,
Nancy Torres,
Jeremy Levin,
Xuemei Du,
Donald Wojciechowicz,
Carolyn Discafani,
Constance Kohler,
Steven C Kim,
Larry R Feldberg,
Karen Collins,
Robert Mallon
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ABSTRACT: 4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)]anilino-6,7-diethoxy-3-quinolinecarbonitrile (3) was identified as a MEK1 kinase inhibitor with exceptional activity against LoVo cells. The structure-activity relationships of the C-4 aniline substituents were explored, and water-solubilizing groups were added at the C-7 position to improve physical properties. Secondary cellular assays revealed that a compound possessing the appropriate aniline substituents inhibited MEK1 as well as MAPK phosphorylation, thereby acting as a dual inhibitor of the Ras-MAPK signaling cascade.
Bioorganic & Medicinal Chemistry Letters 10/2003; 13(18):3031-4. · 2.55 Impact Factor
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ABSTRACT: 4-(2,4-Dichloro-5-methoxy)anilino-5,10-dihydropyrimido[4,5-b]quinolines are potent inhibitors of Src kinase and Src cellular activity while having no effect on Fyn cellular activity. The corresponding 4-(2,4-dichloro-5-methoxy)anilino-pyrimido[4,5-b]quinolines are much less effective Src inhibitors.
Bioorganic & Medicinal Chemistry Letters 10/2003; 13(18):2977-80. · 2.55 Impact Factor
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ABSTRACT: A series of substituted 4-anilino-7-phenyl-3-quinolinecarbonitriles has been prepared as Src kinase inhibitors. Optimal activity is observed with compounds that have basic amines attached via the para position of the 7-phenyl ring, and a hydrogen atom at the C-6 position. The best compounds are low nanomolar inhibitors of Src kinase, and have potent activity against Src-transformed fibroblast cells.
Bioorganic & Medicinal Chemistry Letters 11/2002; 12(20):2989-92. · 2.55 Impact Factor
