8Q61

Co-crystal structure of human AKT2 with compound 3

8Q61 の概要

• エントリーDOI: 10.2210/pdb8q61/pdb
• 分子名称: RAC-beta serine/threonine-protein kinase, 6-[4-(1-azanyl-3-methyl-3-oxidanyl-cyclobutyl)phenyl]-7-phenyl-1-propyl-pyrido[2,3-b][1,4]oxazin-2-one, GLYCEROL, ... (6 entities in total)
• 機能のキーワード: protein kinase inhibitor complex, 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: 56990.57

構造登録者

Harrison, T.,Barker, O. (登録日: 2023-08-10, 公開日: 2023-08-16)

主引用文献

Page, N.,Wappett, M.,O'Dowd, C.R.,O'Rourke, M.,Gavory, G.,Zhang, L.,Rountree, J.S.S.,Jordan, L.,Barker, O.,Gibson, H.,Boyd, C.,Feutren-Burton, S.,McLean, E.,Trevitt, G.,Harrison, T.
Identification and development of a subtype-selective allosteric AKT inhibitor suitable for clinical development.
Sci Rep, 12:15715-, 2022

PubMed Abstract: The serine/threonine protein kinase AKT plays a pivotal role within the PI3K pathway in regulating cellular proliferation and apoptotic cellular functions, and AKT hyper-activation via gene amplification and/or mutation has been implicated in multiple human malignancies. There are 3 AKT isoenzymes (AKT1-3) which mediate critical, non-redundant functions. We present the discovery and development of ALM301, a novel, allosteric, sub-type selective inhibitor of AKT1/2. ALM301 binds in an allosteric pocket created by the combined movement of the PH domain and the catalytic domain, resulting in a DFG out conformation. ALM301 was shown to be highly selective against a panel of over 450 kinases and potently inhibited cellular proliferation. These effects were particularly pronounced in MCF-7 cells containing a PI3KCA mutation. Subsequent cellular downstream pathway analysis in this sensitive cell line revealed potent inhibition of pAKT signalling up to 48 h post dosing. ALM301 treatment was well tolerated in an MCF-7 xenograft model and led to a dose-dependent reduction in tumour growth. Enhanced efficacy was observed in combination with tamoxifen. In summary, ALM301 is a highly specific AKT 1/2 inhibitor with an excellent pharmacological profile suitable for further clinical development.

PubMed: 36127435
DOI: 10.1172/JCI41680

実験手法

X-RAY DIFFRACTION (2.32 Å)