HC-5404 is a differentiated, orally bioavailable investigational small molecule inhibitor of PERK (PKR-like endoplasmic reticulum kinase). PERK is a kinase of the Unfolded Protein Response (UPR), an adaptive cellular program used by cancer cells to survive by facilitating adaptation to harsh tumor microenvironments characterized by hypoxia, nutrient deprivation and oxidative stress. Hypoxia drives the accumulation of misfolded proteins in the endoplasmic reticulum (ER), leading to ER stress and activation of PERK.
Preclinically, we have observed that various standard care cancer therapies further amplify stress in tumors and activate PERK as a survival mechanism. In these settings, we have observed that inhibition of the adaptive UPR via PERK inhibition blocks tumor resistance to standard of care agents, resulting in combinatorial activity in multiple cancer types.