3ML9

Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04691502 through Structure Based Drug Design

3ML9 の概要

• エントリーDOI: 10.2210/pdb3ml9/pdb
• 関連するPDBエントリー: 3ML8
• 分子名称: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, 2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (3 entities in total)
• 機能のキーワード: phosphoinositide kinase, inhibition, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P48736
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 111181.65

構造登録者

Knighton, D.R. (登録日: 2010-04-16, 公開日: 2010-06-02, 最終更新日: 2024-02-21)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.55 Å)