7R26

PI3K delta in complex with SD5

7R26 の概要

• エントリーDOI: 10.2210/pdb7r26/pdb
• 分子名称: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, 5-[2,6-di(morpholin-4-yl)pyrimidin-4-yl]-4-(trifluoromethyl)pyridin-2-amine (3 entities in total)
• 機能のキーワード: kinase, inhibitor, complex, hydrolase
• 由来する生物種: Mus musculus (house mouse)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 108234.06

構造登録者

Gutmann, S.,Rummel, G.,Shrestha, B. (登録日: 2022-02-04, 公開日: 2022-05-18, 最終更新日: 2024-01-31)

主引用文献

Fairhurst, R.A.,Furet, P.,Imbach-Weese, P.,Stauffer, F.,Rueeger, H.,McCarthy, C.,Ripoche, S.,Oswald, S.,Arnaud, B.,Jary, A.,Maira, M.,Schnell, C.,Guthy, D.A.,Wartmann, M.,Kiffe, M.,Desrayaud, S.,Blasco, F.,Widmer, T.,Seiler, F.,Gutmann, S.,Knapp, M.,Caravatti, G.
Identification of NVP-CLR457 as an Orally Bioavailable Non-CNS-Penetrant pan-Class IA Phosphoinositol-3-Kinase Inhibitor.
J.Med.Chem., 65:8345-8379, 2022

PubMed Abstract: Balanced pan-class I phosphoinositide 3-kinase inhibition as an approach to cancer treatment offers the prospect of treating a broad range of tumor types and/or a way to achieve greater efficacy with a single inhibitor. Taking buparlisib as the starting point, the balanced pan-class I PI3K inhibitor (NVP-CLR457) was identified with what was considered to be a best-in-class profile. Key to the optimization to achieve this profile was eliminating a microtubule stabilizing off-target activity, balancing the pan-class I PI3K inhibition profile, minimizing CNS penetration, and developing an amorphous solid dispersion formulation. A rationale for the poor tolerability profile of in a clinical study is discussed.

PubMed: 35500094
DOI: 10.1021/acs.jmedchem.2c00267

実験手法

X-RAY DIFFRACTION (2.3 Å)