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Selectivity in Cells May Vary

The Chemical Probes Portal’s >30‑fold selectivity rule, originally based on cell‑free assays, is challenged by a new open‑access J. Med. Chem. study comparing DiscoverX kinase panels with NanoBRET cellular profiling. Researchers found that most inhibitors appear less potent in living cells, due to factors such as ATP competition, membrane permeability, and full‑length protein context, though a few kinases show heightened cellular sensitivity. Notably, cabozantinib engages the immuno‑oncology target PIP4K2C at mid‑nanomolar levels, while several approved drugs unexpectedly bind the tumor suppressor STK11. The work also proposes new selective probes for understudied kinases BRSK1/2 and DDR1/2.