In an effort to develop clinical compounds for Diffused Intrinsic Pontine Glioma (DIPG) treatment, new analogues of ACVR1/ALK2 inhibitors are continuously synthesised by Ontario Institute for Cancer Research (OICR) and Charles River Laboratories (CRL). I will provide prompt feedback of the cellular assay results to guide their design of new compounds.
I determined the potency of 24 new ACVR1/ALK2 inhibitors synthesised by OICR. M4K2009 in particular is quite potent (larger values indicates lower potency). This compound differs from legacy compound M4K1055 by the position of its methyl group (CH3) in the middle of the molecule. Attempts to replace the tri-methoxy group (the three CH3-O groups bonded to the phenyl ring) were not successful. Since a robust nanoBRET tracer is not available for TGFBR1/ALK5, I will use dual luciferase promoter assay (orthologous assay) to determine the off-target activity of these compounds towards TGFBR1/ALK5.
The M4K monthly meeting where this result was presented has been recorded and posted on youtube.
For detailed experimental protocols, please refer to my Zenodo page.