2. Academic Validation
  3. Identification and development of a subtype-selective allosteric AKT inhibitor suitable for clinical development

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

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. timothy.harrison@almacgroup.com.
  • 8 Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, BT9 7AE, Northern Ireland, UK. timothy.harrison@almacgroup.com.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-151504
    99.33%, AKT1/2抑制剂
    Akt
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