5HKM

DISCOVERY OF NOVEL 7-AZAINDOLES AS PDK1 INHIBITORS

5HKM の概要

• エントリーDOI: 10.2210/pdb5hkm/pdb
• 分子名称: 3-phosphoinositide-dependent protein kinase 1, SULFATE ION, 4-ethyl-6-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-2-amine, ... (4 entities in total)
• 機能のキーワード: pdk1 inhibitor, transferase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: O15530
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35925.07

構造登録者

Wucherer-Plietker, M.,Esdar, C.,Knoechel, T.,Hillertz, P.,Heinrich, T.,Buchstaller, H.P.,Greiner, H.,Dorsch, D.,Calderini, M.,Bruge, D.,Mueller, T.J.J.,Graedler, U. (登録日: 2016-01-14, 公開日: 2016-06-08, 最終更新日: 2024-10-23)

主引用文献

Wucherer-Plietker, M.,Merkul, E.,Muller, T.J.,Esdar, C.,Knochel, T.,Heinrich, T.,Buchstaller, H.P.,Greiner, H.,Dorsch, D.,Finsinger, D.,Calderini, M.,Bruge, D.,Gradler, U.
Discovery of novel 7-azaindoles as PDK1 inhibitors.
Bioorg.Med.Chem.Lett., 26:3073-3080, 2016

PubMed Abstract: A combined screening strategy using HTS together with focused kinase library and virtual screening led to the identification of diverse chemical series as PDK1 inhibitors. We focused our medicinal chemistry efforts on 7-azaindoles with low micromolar IC50s (e.g., 16: IC50=1.1μM) in the biochemical PDK1 assay. Our structure-guided optimization efforts considered also PDK1 X-ray structures with weaker binding fragments and resulted in 7-azaindoles with significantly improved biochemical PDK1 potency in the two-digit nanomolar range. However, the most potent analogues only showed moderate activities in a cellular mechanistic assay (42: IC50=2.3μM) together with either low microsomal stability or low permeability. The described structure-activity relationship together with PDK1 X-ray structures and early ADME data provided the basis for our subsequent hit-to-lead program.

PubMed: 27217002
DOI: 10.1016/j.bmcl.2016.05.005

実験手法

X-RAY DIFFRACTION (2.1 Å)