Brad Herberich

Publications (2)9.6 Total impact

• Article: Selective Class I Phosphoinositide 3-Kinase Inhibitors: Optimization of a Series of Pyridyltriazines Leading to the Identification of a Clinical Candidate, AMG 511.

  Mark H Norman, Kristin L Andrews, Yunxin Y Bo, Shon K Booker, Sean Caenepeel, Victor J Cee, Noel D D'Angelo, Daniel J Freeman, Bradley J Herberich, Fang-Tsao Hong, [......], Nuria A Tamayo, Ling Wang, Douglas A Whittington, Bin Wu, Tian Wu, Ryan P Wurz, Kevin Yang, Leeanne Zalameda, Nancy Zhang, Paul E Hughes
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  ABSTRACT: The phosphoinositide 3-kinase family catalyzes the phosphorylation of phosphatidylinositol-4,5-diphosphate to phosphatidylinositol-3,4,5-triphosphate, a secondary messenger which plays a critical role in important cellular functions such as metabolism, cell growth, and cell survival. Our efforts to identify potent, efficacious, and orally available phosphatidylinositol 3-kinase (PI3K) inhibitors as potential cancer therapeutics have resulted in the discovery of 4-(2-((6-methoxypyridin-3-yl)amino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (1). In this paper, we describe the optimization of compound 1, which led to the design and synthesis of pyridyltriazine 31, a potent pan inhibitor of class I PI3Ks with a superior pharmacokinetic profile. Compound 31 was shown to potently block the targeted PI3K pathway in a mouse liver pharmacodynamic model and inhibit tumor growth in a U87 malignant glioma glioblastoma xenograft model. On the basis of its excellent in vivo efficacy and pharmacokinetic profile, compound 31 was selected for further evaluation as a clinical candidate and was designated AMG 511.
  Journal of Medicinal Chemistry 08/2012; 55(17):7796-816. · 4.80 Impact Factor
• Article: Structure-based design of a novel series of potent, selective inhibitors of the class I phosphatidylinositol 3-kinases.

  Adrian L Smith, Noel D D'Angelo, Yunxin Y Bo, Shon K Booker, Victor J Cee, Brad Herberich, Fang-Tsao Hong, Claire L M Jackson, Brian A Lanman, Longbin Liu, [......], Jian Jiang, Raju Subramanian, Erin L Mullady, Sean Caenepeel, Daniel J Freeman, Ling Wang, Nancy Zhang, Tian Wu, Paul E Hughes, Mark H Norman
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  ABSTRACT: A highly selective series of inhibitors of the class I phosphatidylinositol 3-kinases (PI3Ks) has been designed and synthesized. Starting from the dual PI3K/mTOR inhibitor 5, a structure-based approach was used to improve potency and selectivity, resulting in the identification of 54 as a potent inhibitor of the class I PI3Ks with excellent selectivity over mTOR, related phosphatidylinositol kinases, and a broad panel of protein kinases. Compound 54 demonstrated a robust PD-PK relationship inhibiting the PI3K/Akt pathway in vivo in a mouse model, and it potently inhibited tumor growth in a U-87 MG xenograft model with an activated PI3K/Akt pathway.
  Journal of Medicinal Chemistry 05/2012; 55(11):5188-219. · 4.80 Impact Factor