ml300309h_si_001.pdf (60.46 kB)
Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04979064 through Structure-Based Drug Design
journal contribution
posted on 2013-01-10, 00:00 authored by Hengmiao Cheng, Chunze Li, Simon Bailey, Sangita
M. Baxi, Lance Goulet, Lisa Guo, Jacqui Hoffman, Ying Jiang, Theodore Otto Johnson, Ted W. Johnson, Daniel R. Knighton, John Li, Kevin K.-C. Liu, Zhengyu Liu, Matthew
A. Marx, Marlena Walls, Peter A. Wells, Min-Jean Yin, Jinjiang Zhu, Michael ZientekPI3K, AKT, and mTOR are key kinases
from PI3K signaling pathway
being extensively pursued to treat a variety of cancers in oncology.
To search for a structurally differentiated back-up candidate to PF-04691502,
which is currently in phase I/II clinical trials for treating solid
tumors, a lead optimization effort was carried out with a tricyclic
imidazo[1,5]naphthyridine series. Integration of structure-based drug
design and physical properties-based optimization yielded a potent
and selective PI3K/mTOR dual kinase inhibitor PF-04979064. This manuscript
discusses the lead optimization for the tricyclic series, which both
improved the in vitro potency and addressed a number of ADMET issues
including high metabolic clearance mediated by both P450 and aldehyde
oxidase (AO), poor permeability, and poor solubility. An empirical
scaling tool was developed to predict human clearance from in vitro
human liver S9 assay data for tricyclic derivatives that were AO substrates.