8Q61
Co-crystal structure of human AKT2 with compound 3
Summary for 8Q61
| Entry DOI | 10.2210/pdb8q61/pdb |
| Descriptor | 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) |
| Functional Keywords | protein kinase inhibitor complex, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 56990.57 |
| Authors | |
| Primary citation | 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 Cited by 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: 36127435DOI: 10.1172/JCI41680 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.32 Å) |
Structure validation
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