4dk5

Publication Abstract from PubMed

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 1, a structure-based approach was used to improve potency and selectivity resulting in the identification of 50 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 50 demonstrated a robust PD-PK relationship inhibiting the PI3K/Akt pathway in vivo in a mouse model, and potently inhibited tumor growth in a U 87 MG xenograft model with an activated PI3K/Akt pathway.

Structure-Based Design of a Novel Series of Potent, Selective Inhibitors of the Class I Phosphatidylinositol 3-Kinases.,Smith AL, D'Angelo ND, Bo YY, Booker SK, Cee VJ, Herberich B, Hong FT, Jackson CL, Lanman BA, Liu L, Nishimura N, Pettus LH, Reed AB, Tadesse S, Tamayo NA, Wurz RP, Yang K, Andrews KL, Whittington DA, McCarter JD, San Miguel T, Zalameda L, Jiang J, Subramanian R, Mullady EL, Caenepeel S, Freeman DJ, Wang L, Zhang N, Wu T, Hughes PE, Norman MH J Med Chem. 2012 May 1. PMID:22548365^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.