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

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• The serine/threonine protein kinase AKT is crucial in the PI3K pathway, regulating cell proliferation and apoptosis.
• Hyper-activation of AKT, through gene amplification or mutation, is linked to various human cancers.
• Three AKT isoenzymes (AKT1-3) perform critical, distinct functions.

Purpose of the Study:

• To introduce ALM301, a novel, allosteric, and subtype-selective inhibitor targeting AKT1 and AKT2.
• To characterize the mechanism of action and pharmacological profile of ALM301.

Main Methods:

• ALM301's binding mechanism was determined through structural analysis, revealing an allosteric pocket and DFG-out conformation.
• Kinase selectivity was assessed against over 450 kinases.
• Cellular proliferation and downstream signaling (pAKT) were evaluated in cancer cell lines (MCF-7) and xenograft models.
• Combination therapy efficacy with tamoxifen was investigated.

Main Results:

• ALM301 demonstrated high selectivity and potent inhibition of cellular proliferation, particularly in PI3KCA-mutated MCF-7 cells.
• Significant inhibition of pAKT signaling was observed for up to 48 hours post-treatment.
• ALM301 was well-tolerated in an MCF-7 xenograft model, causing dose-dependent tumor growth reduction.
• Combination with tamoxifen enhanced efficacy.

Conclusions:

• ALM301 is a highly specific AKT 1/2 inhibitor with a favorable pharmacological profile.
• Its potent anti-proliferative and anti-tumor effects, along with good tolerability, support further clinical development.
• ALM301 shows potential as a targeted therapy for cancers driven by AKT hyper-activation, especially in combination regimens.