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J Med Chem. 2012 Jun 14;55(11):5188-219. doi: 10.1021/jm300184s. Epub 2012 May 23.

Structure-based design of a novel series of potent, selective inhibitors of the class I phosphatidylinositol 3-kinases.

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Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.


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.

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