Identification and development of a subtype-selective allosteric AKT inhibitor suitable for clinical development

• Published in: Scientific reports Vol. 12; no. 1; p. 15715
• Main Authors: Page, Natalie, Wappett, Mark, O’Dowd, Colin R., O’Rourke, Martin, Gavory, Gerald, Zhang, Lixin, Rountree, J. S. Shane, Jordan, Linda, Barker, Oliver, Gibson, Hayley, Boyd, Caroline, Feutren-Burton, Stephanie, McLean, Estelle, Trevitt, Graham, Harrison, Timothy
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.09.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 1-Phosphatidylinositol 3-kinase; 631/154; 692/4028; AKT protein; AKT1 protein; Allosteric properties; Apoptosis; Cell proliferation; Dosage; Gene amplification; Humanities and Social Sciences; Isoenzymes; Kinases; multidisciplinary; Mutation; Protein kinase; Protein structure; Protein-serine/threonine kinase; Science; Science (multidisciplinary); Signal transduction; Tumors; Xenografts
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-20208-5

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.