CCT020312

CCT020312 is a selective small molecule activator of the PERK (protein kinase RNA-like endoplasmic reticulum kinase) pathway, specifically targeting the eIF2α/PERK signaling cascade. It functions by promoting phosphorylation of eIF2α, a key downstream substrate of PERK, leading to activation of the unfolded protein response (UPR). This compound activates the PERK/eIF2α/ATF4/CHOP signaling pathway in a dose- and time-dependent manner, inducing apoptosis, cell cycle arrest at the G1 phase, and autophagy. In cancer cells, CCT020312's activation of PERK signaling blocks translation of cyclin D1 and cyclin-dependent kinases (CDK4 and CDK6), resulting in G1 phase cell cycle arrest. It also modulates apoptosis-related proteins by increasing pro-apoptotic factors (Bax, cleaved PARP) and decreasing anti-apoptotic proteins (Bcl-2). Additionally, it inhibits the AKT/mTOR signaling pathway. CCT020312 has demonstrated anti-tumor effects in triple-negative breast cancer, colorectal cancer, prostate cancer, and glioma. Beyond oncology, CCT020312 exhibits neuroprotective effects in neurological conditions. It ameliorated progressive supranuclear palsy and provided neuroprotection in ischemic stroke models by activating the PERK/p-eIF2α pathway and enhancing autophagy signaling. The compound also shows potential in neurodegenerative diseases such as Alzheimer's disease and Huntington's disease by mitigating tau pathology. Pharmacologically, CCT020312 demonstrates potent antiproliferative activity at low millimolar concentrations, with an EC50 of 5.1 μM for PERK activation. It also exhibits chemo-sensitizing activity in osteosarcoma cells.