6HHF

Crystal Structure of AKT1 in Complex with Covalent-Allosteric AKT Inhibitor Borussertib

6HHF の概要

• エントリーDOI: 10.2210/pdb6hhf/pdb
• 分子名称: RAC-alpha serine/threonine-protein kinase, Borussertib (3 entities in total)
• 機能のキーワード: akt1, borussertib, covalent-allosteric, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 52344.73

構造登録者

Landel, I.,Weisner, J.,Mueller, M.P.,Scheinpflug, R.,Rauh, D. (登録日: 2018-08-28, 公開日: 2019-03-20, 最終更新日: 2024-10-23)

主引用文献

Weisner, J.,Landel, I.,Reintjes, C.,Uhlenbrock, N.,Trajkovic-Arsic, M.,Dienstbier, N.,Hardick, J.,Ladigan, S.,Lindemann, M.,Smith, S.,Quambusch, L.,Scheinpflug, R.,Depta, L.,Gontla, R.,Unger, A.,Muller, H.,Baumann, M.,Schultz-Fademrecht, C.,Gunther, G.,Maghnouj, A.,Muller, M.P.,Pohl, M.,Teschendorf, C.,Wolters, H.,Viebahn, R.,Tannapfel, A.,Uhl, W.,Hengstler, J.G.,Hahn, S.A.,Siveke, J.T.,Rauh, D.
Preclinical Efficacy of Covalent-Allosteric AKT Inhibitor Borussertib in Combination with Trametinib inKRAS-Mutant Pancreatic and Colorectal Cancer.
Cancer Res., 79:2367-2378, 2019

PubMed Abstract: Aberrations within the PI3K/AKT signaling axis are frequently observed in numerous cancer types, highlighting the relevance of these pathways in cancer physiology and pathology. However, therapeutic interventions employing AKT inhibitors often suffer from limitations associated with target selectivity, efficacy, or dose-limiting effects. Here we present the first crystal structure of autoinhibited AKT1 in complex with the covalent-allosteric inhibitor borussertib, providing critical insights into the structural basis of AKT1 inhibition by this unique class of compounds. Comprehensive biological and preclinical evaluation of borussertib in cancer-related model systems demonstrated a strong antiproliferative activity in cancer cell lines harboring genetic alterations within the PTEN, PI3K, and RAS signaling pathways. Furthermore, borussertib displayed antitumor activity in combination with the MEK inhibitor trametinib in patient-derived xenograft models of mutant pancreatic and colon cancer. SIGNIFICANCE: Borussertib, a first-in-class covalent-allosteric AKT inhibitor, displays antitumor activity in combination with the MEK inhibitor trametinib in patient-derived xenograft models and provides a starting point for further pharmacokinetic/dynamic optimization.

PubMed: 30858154
DOI: 10.1158/0008-5472.CAN-18-2861

実験手法

X-RAY DIFFRACTION (2.9 Å)