HC-5404 (LY-4) is a potent, selective and orally active inhibitor of PKR-like endoplasmic reticulum kinase (PERK, EIF2AK3) with IC50 of 1 nM.
HC-5404 displays >2000-fold biochemical selectivity against the other integrated stress response (ISR) kinases GCN2 (EIF2AK4), HRI (EIF2AK1), and PKR (EIF2AK2) (IC50>2,000 nM), and excellent selectivity against a KINOMEScan binding panel assay with 468 unique kinases.
HC-5404 potently inhibits tunicamycin (1 uM) induced ER stress in HEK-293 cells, inhibits PERK autophosphorylation at Thr982 (pPERK) and suppresses ATF4 levels with IC50 of 23 nM and 88 nM, respectively.
HC-5404 (30 mg/kg, orally BID) suppress tumor growth in the 786-O xenograft model of RCC.
Cotreatment with HC-5404 inhibited PERK in tumors and significantly increased antitumor effects of VEGFR-TKIs across multiple RCC models, resulting in tumor stasis or regression.
