Yongbo Hu

Publications (14)42.47 Total impact

• Article: Structure-based design of isoindoline-1,3-diones and 2,3-dihydrophthalazine-1,4-diones as novel B-Raf inhibitors.

  Xiaolun Wang, Edward J Salaski, Dan M Berger, Dennis Powell, Yongbo Hu, Donald Wojciechowicz, Karen Collins, Eileen Frommer
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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
• Article: Macrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity.

  Christoph W Zapf, Jonathan D Bloom, Jamie L McBean, Russell G Dushin, Thomas Nittoli, Mercy Otteng, Charles Ingalls, Jennifer M Golas, Hao Liu, Judy Lucas, Frank Boschelli, Yongbo Hu, Erik Vogan, Jeremy I Levin
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  ABSTRACT: A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research in this area, macrocyclic amides and lactams were explored to reduce the risk of hERG liabilities. This effort culminated in the discovery of compound 38, which showed a favorable in vitro profile, and efficiently suppressed proliferation of several relevant cell lines. This compound showed prolonged Hsp90-inhibitory activity at least 24 h post-administration, consistent with elevated and prolonged exposure in the tumor.
  Bioorganic & medicinal chemistry letters 06/2011; 21(11):3411-6. · 2.65 Impact Factor
• Article: Design and SAR of macrocyclic Hsp90 inhibitors with increased metabolic stability and potent cell-proliferation activity.

  Christoph W Zapf, Jonathan D Bloom, Jamie L McBean, Russell G Dushin, Thomas Nittoli, Charles Ingalls, Alan G Sutherland, John P Sonye, Clark N Eid, Jennifer Golas, Hao Liu, Frank Boschelli, Yongbo Hu, Erik Vogan, Jeremy I Levin
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  ABSTRACT: A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. A basic nitrogen within the tether linking the aniline nitrogen atom to a tetrahydroindolone moiety allowed access to compounds with good physical properties. Important structure-activity relationship information was obtained from this series which led to the discovery of a soluble and stable compound which is potent in an Hsp90 binding and cell-proliferation assay.
  Bioorganic & medicinal chemistry letters 02/2011; 21(8):2278-82. · 2.65 Impact Factor
• Article: Indazolylpyrazolopyrimidine as highly potent B-Raf inhibitors with in vivo activity.

  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
• Article: The identification of 8,9-dimethoxy-5-(2-aminoalkoxy-pyridin-3-yl)-benzo[c][2,7]naphthyridin-4-ylamines as potent inhibitors of 3-phosphoinositide-dependent kinase-1 (PDK-1).

  Thomas Nittoli, Russell G Dushin, Charles Ingalls, Katherine Cheung, M Brawner Floyd, Heidi Fraser, Andrea Olland, Yongbo Hu, George Grosu, Xin Han, Kim Arndt, Bing Guo, Allan Wissner
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  ABSTRACT: A series of 8,9-dimethoxy-5-(2-aminoalkoxy-pyridin-3-yl)-benzo[c][2,7]naphthyridin-4-ylamine-based inhibitors of 3-phosphoinositide-dependent kinase-1 (PDK-1) has been identified. Several examples appear to be potent and relatively selective inhibitors of PDK-1 over the related AGC kinases PKA, PKB/AKT, and p70S6K. The introduction of a stereochemical center beside the amino substituent on the aminoalkoxy-side chain had little effect upon the inhibitory activity against these enzymes, and X-ray crystallographic analyses of a representative pair of enantiomeric inhibitors bound to the active site of PDK-1 revealed comparable binding modes for each enantiomer.
  European journal of medicinal chemistry 04/2010; 45(4):1379-86. · 3.27 Impact Factor
• Article: B-Raf kinase inhibitors: hit enrichment through scaffold hopping.

  Ariamala Gopalsamy, Mengxiao Shi, Yongbo Hu, Frederick Lee, Larry Feldberg, Eileen Frommer, Steven Kim, Karen Collins, Donald Wojciechowicz, Robert Mallon
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  ABSTRACT: In continuation of our efforts toward hit identification and optimization for a B-Raf kinase project, we have employed a scaffold hopping strategy. The original HTS hit scaffold pyrazolo[1,5-a]pyrimidine was replaced with different thienopyrimidine and thienopyridine scaffolds to append the optimal pharmacophore moieties in order to generate novel B-raf kinase inhibitors with desirable potency and properties. This strategy led to the identification of additional lead compound 11b which had good enzyme and cell potency, while maintaining selectivity over a number of kinases.
  Bioorganic & medicinal chemistry letters 03/2010; 20(8):2431-4. · 2.65 Impact Factor
• Article: Non-hinge-binding pyrazolo[1,5-a]pyrimidines as potent B-Raf kinase inhibitors.

  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
• Article: Discovery of highly potent and selective type I B-Raf kinase inhibitors.

  Xiaolun Wang, Dan M Berger, Edward J Salaski, Nancy Torres, Yongbo Hu, Jeremy I Levin, Dennis Powell, Donald Wojciechowicz, Karen Collins, Eileen Frommer
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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
• Article: Hit to lead optimization of pyrazolo[1,5-a]pyrimidines as B-Raf kinase inhibitors.

  Ariamala Gopalsamy, Greg Ciszewski, Mengxiao Shi, Dan Berger, Yongbo Hu, Frederick Lee, Larry Feldberg, Eileen Frommer, Steven Kim, Karen Collins, Donald Wojciechowicz, Robert Mallon
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  ABSTRACT: Our continued effort towards optimization of the pyrazolo[1,5-a]pyrimidine scaffold as B-Raf kinase inhibitors is described. Structure guided design was utilized to introduce kinase hinge region interacting groups in the 2-position of the scaffold. This strategy led to the identification of lead compound 9 with enhanced enzyme and cellular potency, while maintaining good selectivity over a number of kinases.
  Bioorganic & medicinal chemistry letters 10/2009; 19(24):6890-2. · 2.65 Impact Factor
• Article: Small molecule inhibitors of HIV RT Ribonuclease H.

  Martin Di Grandi, Matthew Olson, Amar S Prashad, Geraldine Bebernitz, Amara Luckay, Stanley Mullen, Yongbo Hu, Girija Krishnamurthy, Keith Pitts, John O'Connell
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  ABSTRACT: Two classes of compounds, thiocarbamates 1 and triazoles 2, have been identified as HIV RT RNase H inhibitors using a novel FRET-based HTS assay. The potent analogs in each series exhibited selectivity and were active in cell-based assays. In addition, saturable, 1:1 stoichiometric binding to target was established and time of addition studies were consistent with inhibition of RT-mediated HIV replication.
  Bioorganic & medicinal chemistry letters 10/2009; 20(1):398-402. · 2.65 Impact Factor
• Article: Novel pyrazolopyrimidines as highly potent B-Raf inhibitors.

  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
• Article: Benzo[c][2,7]naphthyridines as inhibitors of PDK-1.

  Kyung-Hee Kim, Allan Wissner, Middleton B Floyd, Heidi L Fraser, Yanong D Wang, Russell G Dushin, Yongbo Hu, Andrea Olland, Bing Guo, Kim Arndt
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  ABSTRACT: A series of substituted benzo[c][2,7]-naphthyridines were prepared and showed good potency in inhibiting PDK-1. The synthesis and SAR of this series of compounds are presented as well as the X-ray crystal structure of one of these analogs in a complex with PDK-1.
  Bioorganic & medicinal chemistry letters 08/2009; 19(17):5225-8. · 2.65 Impact Factor
• Article: Identification of pyrazolo[1,5-a]pyrimidine-3-carboxylates as B-Raf kinase inhibitors.

  Ariamala Gopalsamy, Greg Ciszewski, Yongbo Hu, Frederick Lee, Larry Feldberg, Eileen Frommer, Steven Kim, Karen Collins, Donald Wojciechowicz, Robert Mallon
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  ABSTRACT: B-Raf kinase plays a critical role in the Raf-MEK-ERK signaling pathway and inhibitors of B-Raf could be used in the treatment of melanomas, colorectal cancer, and other Ras related human cancers. We have identified novel small molecule pyrazolo[1,5-a]pyrimidine derivatives as B-Raf kinase inhibitors. Structure-activity relationship was generated for various regions of the scaffold to improve the biochemical profile.
  Bioorganic & medicinal chemistry letters 04/2009; 19(10):2735-8. · 2.65 Impact Factor
• Article: Discovery of dibenzo[c,f][2,7]naphthyridines as potent and selective 3-phosphoinositide-dependent kinase-1 inhibitors.

  Ariamala Gopalsamy, Mengxiao Shi, Diane H Boschelli, Robert Williamson, Andrea Olland, Yongbo Hu, Girija Krishnamurthy, Xin Han, Kim Arndt, Bing Guo
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  ABSTRACT: With high-throughput screening, substituted dibenzo[c,f][2,7]naphthyridine 1 was identified as a novel potent and selective phosphoinositide-dependent kinase-1 (PDK-1) inhibitor. Various regions of the lead molecule were explored to understand the SAR requirement for this scaffold. The crystal structure of 1 with kinase domain of PDK-1 confirmed the binding in the active site. The key interaction of the molecule with the active site residues, observed SAR, and the biological profile are discussed in detail.
  Journal of Medicinal Chemistry 12/2007; 50(23):5547-9. · 5.25 Impact Factor