Jonas Grina

Publications (9)22.49 Total impact

• Article: The discovery of potent and selective pyridopyrimidin-7-one based inhibitors of B-RafV600E kinase.

  Li Ren, Kateri A Ahrendt, Jonas Grina, Ellen R Laird, Alex J Buckmelter, Joshua D Hansen, Brad Newhouse, David Moreno, Steve Wenglowsky, Victoria Dinkel, Susan L Gloor, Gregg Hastings, Sumeet Rana, Kevin Rasor, Tyler Risom, Hillary L Sturgis, Walter C Voegtli, Simon Mathieu
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  ABSTRACT: Herein we describe the discovery of a novel series of ATP competitive B-Raf inhibitors via structure based drug design (SBDD). These pyridopyrimidin-7-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 17, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies.
  Bioorganic & medicinal chemistry letters 04/2012; 22(10):3387-91. · 2.65 Impact Factor
• Article: Potent and selective aminopyrimidine-based B-Raf inhibitors with favorable physicochemical and pharmacokinetic properties.

  Simon Mathieu, Stefan N Gradl, Li Ren, Zhaoyang Wen, Ignacio Aliagas, Janet Gunzner-Toste, Wendy Lee, Rebecca Pulk, Guiling Zhao, Bruno Alicke, [......], Joshua D Hansen, Gregg Hastings, Georgia Hatzivassiliou, Ellen R Laird, David Moreno, Yingqing Ran, Walter C Voegtli, Steve Wenglowsky, Jonas Grina, Joachim Rudolph
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  ABSTRACT: Recent clinical data provided proof-of-concept for selective B-Raf inhibitors in treatment of B-Raf(V600E) mutant melanoma. Pyrazolopyridine-type B-Raf inhibitors previously described by the authors are potent and selective but exhibit low solubility requiring the use of amorphous dispersion-based formulation for achieving efficacious drug exposures. Through structure-based design, we discovered a new class of highly potent aminopyrimidine-based B-Raf inhibitors with improved solubility and pharmacokinetic profiles. The hinge binding moiety possesses a basic center imparting high solubility at gastric pH, addressing the dissolution limitation observed with our previous series. In our search for an optimal linker-hinge binding moiety system, amide-linked thieno[3,2-d]pyrimidine analogues 32 and 35 (G945), molecules with desirable physicochemical properties, emerged as lead compounds with strong efficacy in a B-Raf(V600E) mutant mouse xenograft model. Synthesis, SAR, lead selection, and evaluation of key compounds in animal studies will be described.
  Journal of Medicinal Chemistry 02/2012; 55(6):2869-81. · 4.80 Impact Factor
• Article: Potent and selective pyrazolo[1,5-a]pyrimidine based inhibitors of B-Raf(V600E) kinase with favorable physicochemical and pharmacokinetic properties.

  Li Ren, Ellen R Laird, Alex J Buckmelter, Victoria Dinkel, Susan L Gloor, Jonas Grina, Brad Newhouse, Kevin Rasor, Gregg Hastings, Stefan N Gradl, Joachim Rudolph
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  ABSTRACT: Herein we describe a novel series of ATP competitive B-Raf inhibitors based on the pyrazolo[1,5-a]pyrimidine scaffold. These inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 17, a potent, selective and orally available agent with improved physicochemical and pharmacokinetic properties.
  Bioorganic & medicinal chemistry letters 11/2011; 22(2):1165-8. · 2.65 Impact Factor
• Article: Pyrazolopyridine inhibitors of B-RafV600E. Part 2: structure-activity relationships.

  Steve Wenglowsky, Kateri A Ahrendt, Alex J Buckmelter, Bainian Feng, Susan L Gloor, Stefan Gradl, Jonas Grina, Joshua D Hansen, Ellen R Laird, Paul Lunghofer, Simon Mathieu, David Moreno, Brad Newhouse, Li Ren, Tyler Risom, Joachim Rudolph, Jeongbeob Seo, Hillary L Sturgis, Walter C Voegtli, Zhaoyang Wen
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  ABSTRACT: Structure-activity relationships around a novel series of B-Raf(V600E) inhibitors are reported. The enzymatic and cellular potencies of inhibitors derived from two related hinge-binding groups were compared and3-methoxypyrazolopyridine proved to be superior. The 3-alkoxy group of lead B-Raf(V600E) inhibitor 1 was extended and minimally affected potency. The propyl sulfonamide tail of compound 1, which occupies the small lipophilic pocket formed by an outward shift of the αC-helix, was expanded to a series of arylsulfonamides. X-ray crystallography revealed that this lipophilic pocket unexpectedly enlarges to accommodate the bulkier aryl group.
  Bioorganic & medicinal chemistry letters 09/2011; 21(18):5533-7. · 2.65 Impact Factor
• Article: Preclinical assessment of novel BRAF inhibitors: integrating pharmacokinetic-pharmacodynamic modelling in the drug discovery process.

  Edna F Choo, Bruno Alicke, Jason Boggs, Vikki Dinkel, Stephen Gould, Jonas Grina, Kristina West, Kapil Menghrajani, Yingqing Ran, Joachim Rudolph, Steve Wenglowsky
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  ABSTRACT: The objective of these studies were to determine the preclinical disposition of the two BRAF inhibitors, G-F and G-C, followed by pharmacokinetic (PK)-pharmacodynamic (PD) modelling to characterize the concentration-efficacy relationship of these compounds in the Colo205 mouse xenograft model. With G-F, the relationship of pERK inhibition to concentration was also characterized. Compounds G-F and G-C were administered to mice, rats and dogs and the pharmacokinetics of G-F and G-C was determined. In addition, using indirect response models the concentration-efficacy relationship was described. The clearance of G-F was low; 0.625 and 4.65 mL/min/kg in rat and dog respectively. Similarly, the clearance of G-C was low in rat and dog, 0.490 and 4.43 mL/min/kg, respectively. Both compounds displayed low volumes of distribution (0.140-0.267 L/kg), resulting in moderate half-lives across species (~2.5 to 4 h). Bioavailability was formulation dependent and decreased with increasing dose. Using the indirect response models, the KC(50) (50% K(max); maximal response) value for tumor growth inhibition for G-F and G-C were 84.5 and 19.2 μM, respectively. The IC(50) for pERK inhibition in Colo205 tumors by G-F was estimated to be 29.2 μM. High exposures of G-F and G-C were required for efficacy. Despite good PK properties of low CL and moderate half-life, limitations in obtaining exposures adequate for safety testing in rat and dog resulted in development challenges.
  Xenobiotica 08/2011; 41(12):1076-87. · 1.79 Impact Factor
• Article: Non-oxime pyrazole based inhibitors of B-Raf kinase.

  Bradley J Newhouse, Joshua D Hansen, Jonas Grina, Mike Welch, George Topalov, Nicole Littman, Michele Callejo, Matthew Martinson, Sarah Galbraith, Ellen R Laird, Barbara J Brandhuber, Guy Vigers, Tony Morales, Rich Woessner, Nikole Randolph, Joseph Lyssikatos, Alan Olivero
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  ABSTRACT: The synthesis and biological evaluation of non-oxime pyrazole based B-Raf inhibitors is reported. Several oxime replacements have been prepared and have shown excellent enzyme activity. Further optimization of fused pyrazole 2a led to compound 38, a selective and potent B-Raf inhibitor.
  Bioorganic & medicinal chemistry letters 06/2011; 21(11):3488-92. · 2.65 Impact Factor
• Article: Pyrazolopyridine Inhibitors of B-RafV600E. Part 1: The Development of Selective, Orally Bioavailable, and Efficacious Inhibitors

  Steve Wenglowsky, Li Ren, Kateri A. Ahrendt, Ellen R. Laird, Ignacio Aliagas, Bruno Alicke, Alex J. Buckmelter, Edna F. Choo, Victoria Dinkel, Bainian Feng, [......], Michael Shrag, Kyung Song, Hillary L. Sturgis, Walter C. Voegtli, Zhaoyang Wen, Brandon S. Willis, Richard D. Woessner, Wen-I Wu, Wendy B. Young, Jonas Grina
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  ABSTRACT: The V600E mutation of B-Raf kinase results in constitutive activation of the MAPK signaling pathway and is present in approximately 7% of all cancers. Using structure-based design, a novel series of pyrazolopyridine inhibitors of B-RafV600E was developed. Optimization led to the identification of 3-methoxy pyrazolopyridines 17 and 19, potent, selective, and orally bioavailable agents that inhibited tumor growth in a mouse xenograft model driven by B-RafV600E with no effect on body weight. On the basis of their in vivo efficacy and preliminary safety profiles, 17 and 19 were selected for further preclinical evaluation.Keywords: B-RafV600E; MAPK pathway; targeted therapy; pyrazolopyridine; amorphous spray-dried dispersion
  03/2011;
• Article: The discovery of furo[2,3-c]pyridine-based indanone oximes as potent and selective B-Raf inhibitors.

  Alex J Buckmelter, Li Ren, Ellen R Laird, Bryson Rast, Greg Miknis, Steve Wenglowsky, Stephen Schlachter, Mike Welch, Eugene Tarlton, Jonas Grina, Joseph Lyssikatos, Barbara J Brandhuber, Tony Morales, Nikole Randolph, Guy Vigers, Matthew Martinson, Michele Callejo
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  ABSTRACT: Virtual and high-throughput screening identified imidazo[1,2-a]pyrazines as inhibitors of B-Raf. We describe the rationale, SAR, and evolution of the initial hits to a series of furo[2,3-c]pyridine indanone oximes as highly potent and selective inhibitors of B-Raf.
  Bioorganic & medicinal chemistry letters 02/2011; 21(4):1248-52. · 2.65 Impact Factor
• Article: Potent and selective pyrazole-based inhibitors of B-Raf kinase.

  Joshua D Hansen, Jonas Grina, Brad Newhouse, Mike Welch, George Topalov, Nicole Littman, Michele Callejo, Susan Gloor, Matthew Martinson, Ellen Laird, Barbara J Brandhuber, Guy Vigers, Tony Morales, Rich Woessner, Nikole Randolph, Joseph Lyssikatos, Alan Olivero
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  ABSTRACT: Herein we describe a novel pyrazole-based class of ATP competitive B-Raf inhibitors. These inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. A subset of these inhibitors has demonstrated the ability to inhibit downstream ERK phosphorylation in LOX tumors from mouse xenograft studies.
  Bioorganic & medicinal chemistry letters 09/2008; 18(16):4692-5. · 2.65 Impact Factor