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Covalent Allosteric Inhibitors of Akt Generated Using a Click Fragment Approach.

ABSTRACT: Akt is a protein kinase that has been implicated in the progression of cancerous tumours. A number of covalent allosteric Akt inhibitors are known, and based on these scaffolds, a small library of novel potential covalent allosteric imidazopyridine-based inhibitors was designed. The envisaged compounds were synthesised, with click chemistry enabling a modular approach to a number of the target compounds. The binding modes, potencies and antiproliferative activities of these synthesised compounds were explored, thereby furthering the structure activity relationship knowledge of this class of Akt inhibitors. Three novel covalent inhibitors were identified, exhibiting moderate activity against Akt1 and various cancer cell lines, potentially paving the way for future covalent allosteric inhibitors with improved properties.

SUBMITTER: van der Westhuizen L

PROVIDER: S-EPMC9311865 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Covalent Allosteric Inhibitors of Akt Generated Using a Click Fragment Approach.

van der Westhuizen Leandi L Weisner Jörn J Taher Abu A Landel Ina I Quambusch Lena L Lindemann Marius M Uhlenbrock Niklas N Müller Matthias P MP Green Ivan R IR Pelly Stephen C SC Rauh Daniel D van Otterlo Willem A L WAL

ChemMedChem 20220309 10

Akt is a protein kinase that has been implicated in the progression of cancerous tumours. A number of covalent allosteric Akt inhibitors are known, and based on these scaffolds, a small library of novel potential covalent allosteric imidazopyridine-based inhibitors was designed. The envisaged compounds were synthesised, with click chemistry enabling a modular approach to a number of the target compounds. The binding modes, potencies and antiproliferative activities of these synthesised compounds ...[more]

PMID: 35170857

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