Key clinical point: Pre-clinical data suggests a novel class of 3-(6-phenoxypyridin-3-yl)-4-amine-1H-pyrazolo[3,4-d]pyrimidine analogs could have better BTK selectivity than other BTK-inhibitors.
Major finding: One novel drug candidate showed 3- to 40-fold better antiproliferative activity in mantle cell lymphoma (MCL) cell lines compared with ibrutinib.
Study details: A pre-clinical study examining the effects of a novel series of selective BTK inhibitors in MCL.
Disclosures: The study was supported by the key research and development project of Shandong Province (China). No conflicts of interest were reported.
Currently approved BTK inhibitors have several well-described limitations. For example, they are rendered less active by the BTK C481S mutation, which impairs drug binding, and other mechanisms of resistance occur despite a high degree of BTK occupancy. Additionally, existing BTK inhibitors have been associated with unfortunate side effects that frequently result in the discontinuation of treatment. More potent and specific BTK inhibitors may have a theoretical safety advantage over existing BTK inhibitors, but there are several caveats. Drugs that are active in the petri dish still face such challenges as oral bioavailability, protein binding, metabolism, excretion, and drug-drug interactions. In the setting of multiple FDA-approved drugs, with several more novel agents on the way, it will be interesting to see whether sufficient resources are available for the development of new drugs that might be predicted to have a marginally better safety profile.—Peter Martin, MD
Ran F et al. Bioorg Chem. 2019 Oct 15. doi: 10.1016/j.bioorg.2019.103367.