4HVB

Catalytic unit of PI3Kg in complex with PI3K/mTOR dual inhibitor PF-04979064

Summary for 4HVB

• Entry DOI: 10.2210/pdb4hvb/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, 1-{1-[(2S)-2-hydroxypropanoyl]piperidin-4-yl}-3-methyl-8-(6-methylpyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c][1,5]naphthyridin-2-one (3 entities in total)
• Functional Keywords: lipid kinase, kinase, phosphoinositide kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P48736
• Total number of polymer chains: 1
• Total formula weight: 111202.67

Authors

Knighton, D.R.,Cheng, H. (deposition date: 2012-11-05, release date: 2013-11-20, Last modification date: 2024-02-28)

Primary citation

Cheng, H.,Li, C.,Bailey, S.,Baxi, S.M.,Goulet, L.,Guo, L.,Hoffman, J.,Jiang, Y.,Johnson, T.O.,Johnson, T.W.,Knighton, D.R.,Li, J.,Liu, K.K.,Liu, Z.,Marx, M.A.,Walls, M.,Wells, P.A.,Yin, M.J.,Zhu, J.,Zientek, M.
Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04979064 through Structure-Based Drug Design.
ACS Med Chem Lett, 4:91-97, 2013

PubMed Abstract: PI3K, 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.

PubMed: 24900568
DOI: 10.1021/ml300309h

Experimental method

X-RAY DIFFRACTION (2.35 Å)