DNL343

Upon detection of cellular stress, eIF2a becomes phosphorylated. p-eIF2a inhibits the GEF activity of eIF2B, resulting in activation of the integrated stress response (ISR) and stalled protein translation. DNL343 binds to the multi-protein eIF2B complex at the interface between the beta- and gamma-subunits, stabilizing eIF2B and maintaining its GEF activity even in the presence of inhibitory p-eIF2a. This makes DNL343 a molecular glue that allows constitutive activation of eIF2B and repression of the ISR in the presence of cellular stress. Importantly, DNL343 inhibits the ISR no matter the type of cellular stress or the upstream kinase that has phosphorylated eIF2a. DNL34 inhibits the stress-induced expression of an ISR reporter construct and the formation of TDP43+ stress granules with IC50 ~ 10 nM, making it a very potent cellular probe. DNL343 is also brain penetrant and orally bioavailable, and it achieves marked reduction of ISR gene expression in mice dosed once daily at 50 mg/kg PO. DNL343 has no off-target liabilities except for weak inhibition of hERG (IC50 = 3 uM), but cardiac toxicity as a result of this weak hERG inhibition has been de-risked (including in a GMP cardiotox experiment in nonhuman primates). I feel that DNL343 is a best-in-class chemical probe for the inhibition of the ISR both in vitro and in vivo, and it can be confidently used at or below 1 uM in cells.