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

Page, Norbert P.; Wappett, Mark; O'Dowd, Colin; 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, T. Mark

doi:10.1038/s41598-022-20208-5

Cited by 4 publications

(6 citation statements)

References 38 publications

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“…Allosteric inhibitors bind to the inactive closed conformation of Akt by stabilizing the PH-kinase domain interface thus preventing Akt recruitment to the membrane and consequent Akt activation 89 , 95 . By targeting both domains, allosteric inhibitors reveal a high selectivity also among Akt isoforms 96 – 98 .…”

Section: Discussionmentioning

confidence: 99%

Structural investigation of Trypanosoma cruzi Akt-like kinase as drug target against Chagas disease

Stadler,

Ortiz-Joya,

Singh Sahrawat

et al. 2024

Sci Rep

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According to the World Health Organization, Chagas disease (CD) is the most prevalent poverty-promoting neglected tropical disease. Alarmingly, climate change is accelerating the geographical spreading of CD causative parasite, Trypanosoma cruzi, which additionally increases infection rates. Still, CD treatment remains challenging due to a lack of safe and efficient drugs. In this work, we analyze the viability of T. cruzi Akt-like kinase (TcAkt) as drug target against CD including primary structural and functional information about a parasitic Akt protein. Nuclear Magnetic Resonance derived information in combination with Molecular Dynamics simulations offer detailed insights into structural properties of the pleckstrin homology (PH) domain of TcAkt and its binding to phosphatidylinositol phosphate ligands (PIP). Experimental data combined with Alpha Fold proposes a model for the mechanism of action of TcAkt involving a PIP-induced disruption of the intramolecular interface between the kinase and the PH domain resulting in an open conformation enabling TcAkt kinase activity. Further docking experiments reveal that TcAkt is recognized by human inhibitors PIT-1 and capivasertib, and TcAkt inhibition by UBMC-4 and UBMC-6 is achieved via binding to TcAkt kinase domain. Our in-depth structural analysis of TcAkt reveals potential sites for drug development against CD, located at activity essential regions.

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Section: Discussionmentioning

confidence: 99%

Structural investigation of Trypanosoma cruzi Akt-like kinase as drug target against Chagas disease

Stadler,

Ortiz-Joya,

Singh Sahrawat

et al. 2024

Sci Rep

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“…Sometimes, it turned out that the inhibition of AKT2 may be the strongest among the three subtypes. For instance, the IC 50 values of ALM301 against the AKT1, AKT2 and AKT3 were 0.13, 0.09 and 2.75 µM, respectively [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

“…To evaluate the effect of the PH domain on ligand binding to the AKT2 protein, we made a model protein by attaching the PH domain residues to the model protein 3D0E. To properly incorporate the PH domain to 3D0E, we used the solution structure of the PH domain of AKT2 (PDB id: 1P6S) [ 34 ] and the crystal structure of AKT2 (PDB id: 8Q61) [ 51 ]. Structural alignment between 1P6S and 8Q61 was carried out in the MOE program to align the PH domain between 1P6S and 8Q61.…”

Section: Methodsmentioning

confidence: 99%

Selectivity Studies and Free Energy Calculations of AKT Inhibitors

Zhong,

Goodwin

2024

Molecules

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Protein kinase B (PKB) or AKT protein is an important target for cancer treatment. Significant advances have been made in developing ATP-competitive inhibitors and allosteric binders targeting AKT1. However, adverse effects or toxicities have been found, and the cutaneous toxicity was found to be linked to the inhibition of AKT2. Thus, selective inhibition of AKT inhibitors is of significance. Our work, using the Schrödinger Covalent Dock (CovDock) program and the Movable Type (MT)-based free energy calculation (ΔG), yielded small mean errors for the experimentally derived binding free energy (ΔG). The docking data suggested that AKT1 binding may require residues Asn54, Trp80, Tyr272, Asp274, and Asp292, whereas AKT2 binding would expect residues Phe163 and Glu279, and AKT3 binding would favor residues Glu17, Trp79, Phe306, and Glu295. These findings may help guide AKT1-selective or AKT3-selective molecular design while sparing the inhibition of AKT2 to minimize the cutaneous toxicity.

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“…This compound showed potent in vitro inhibition of Akt1/2 in the high nanomolar range, exhibited selectivity across the kinome, and demonstrated powerful antiproliferative effects in cancer cell lines. In vivo experiments further demonstrated VAD-044’s efficacy as a single agent and in combination with tamoxifen in an MCF7 breast cancer xenograft model . Based on promising preclinical results, considering the mechanism of action, ADME, and pharmacokinetic features, VAD-044 is currently undergoing Phase I studies to assess its safety and tolerability in patients with hereditary hemorrhagic telangiectasia (HHT), also known as Osler–Weber–Rendu syndrome (NCT05406362).…”

Section: Allosteric Akt Inhibitorsmentioning

confidence: 99%

Akt Inhibitor Advancements: From Capivasertib Approval to Covalent-Allosteric Promises

Pervanidis,

D’Angelo,

Weisner

et al. 2024

J. Med. Chem.

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Akt kinase is vital in cell growth, survival, metabolism, and migration. Dysregulation of Akt signaling is implicated in cancer and metabolic disorders. In the context of cancer, overactive Akt promotes cell survival and proliferation. This has spurred extensive research into developing Akt inhibitors as potential therapeutic agents to disrupt aberrant Akt signaling. Akt inhibitors are classified into three main types: ATP-competitive, allosteric, and covalent-allosteric inhibitors (CAAIs). ATPcompetitive inhibitors compete with ATP for binding to Akt, allosteric inhibitors interact with the Pleckstrin homology (PH) domain, and covalent-allosteric inhibitors form covalent bonds, making them more potent and selective. Notably, capivasertib (AZD5363), a potent ATP-competitive Akt inhibitor, received FDA approval in November 2023 for use in combination with the estrogen receptor degrader fulvestrant to treat breast cancer. Challenges remain, including improving selectivity, identifying biomarkers to tailor treatments, and enhancing therapeutic efficacy while minimizing adverse effects. Particularly covalent-allosteric inhibitors hold promise for future more effective and personalized treatments. ■ SIGNIFICANCE This Perspective highlights the pivotal role of Akt kinase in cancer and metabolic diseases. It focuses on the landmark FDA approval of capivasertib, a first-generation Akt inhibitor, for the treatment of breast cancer. It heralds the emergence of nextgeneration Akt inhibitors, allosteric and covalent-allosteric, that promise improved selectivity and potency, ushering in a new era of therapeutic strategies and personalized, more effective interventions.

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

Cited by 4 publications

References 38 publications

Structural investigation of Trypanosoma cruzi Akt-like kinase as drug target against Chagas disease

Structural investigation of Trypanosoma cruzi Akt-like kinase as drug target against Chagas disease

Selectivity Studies and Free Energy Calculations of AKT Inhibitors

Akt Inhibitor Advancements: From Capivasertib Approval to Covalent-Allosteric Promises

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