Novel optimization of valmerins (tetrahydropyrido[1,2-a]isoindolones) as potent dual CDK5/GSK3 inhibitors

• A novel Valmerin library was built containing 25 final molecules.
• 16 Valmerins with a CDK5 or GSK3 IC50 between 6 and 100 nM.
• 7 Molecules with a dual kinase inhibition.
• 6 Molecules with cell effects <100 nM.
• Molecules with CDK5 and GSK3 inhibitions/cell effects <100 nM are ready for development.

An efficient synthetic strategy able to modulate the structure of the tetrahydropyridine isoindolone (Valmerin) skeleton was developed. A library of more than 30 novel final structures was generated. Biological activities on CDK5 and GSK3 as well as cellular effects on cancer cell lines were measured for each novel compound. Additionally to support the SAR, a docking study was performed. A potent GSK3/CDK5 dual inhibitor (37, IC50 CDK5/GSK3 35/7 nM) was obtained. Best antiproliferative effects were obtained on lung and prostate cell lines with IC50 = 20 nM.

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