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

  • Sci Rep. 2022 Sep 20;12(1):15715. doi: 10.1038/s41598-022-20208-5.
Natalie Page  1 ,  Mark Wappett  1 ,  Colin R O'Dowd  1 ,  Martin O'Rourke  2 ,  Gerald Gavory  3 ,  Lixin Zhang  4 ,  J S Shane Rountree  1 ,  Linda Jordan  5 ,  Oliver Barker  1 ,  Hayley Gibson  1 ,  Caroline Boyd  1 ,  Stephanie Feutren-Burton  1 ,  Estelle McLean  1 ,  Graham Trevitt  6 ,  Timothy Harrison  7  8
Affiliations
  • 1. Almac Discovery Ltd, Health Sciences Building, 97 Lisburn Road, Belfast, BT9 7AE, Northern Ireland, UK.
  • 2. Amphista Therapeutics, BioCity, Bo'Ness Rd, Newhouse, Chapelhall, Motherwell, ML1 5UH, UK.
  • 3. Ridgeline Therapeutics GmbH, Technologiepark, Hochbergerstrasse 60C, 4057, Basel, Switzerland.
  • 4. Shenyang University of Chemical Technology, Shenyang, China.
  • 5. Globachem, Alderley Park, 2 BioHub, Mereside, Macclesfield, SK10 4TG, UK.
  • 6. Sygnature Discovery, BioCity, Pennyfoot Street, Nottingham, NG1 1GR, UK.
  • 7. Almac Discovery Ltd, Health Sciences Building, 97 Lisburn Road, Belfast, BT9 7AE, Northern Ireland, UK. [email protected].
  • 8. Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, BT9 7AE, Northern Ireland, UK. [email protected].
PMID: 36127435 DOI: 10.1038/s41598-022-20208-5
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.

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