Lim, Jin Hong Park, Keunwan Choi, Kyung Hwa Kim, Jungmin Jhe, Yoo-Lim Kim, Seok-Mo Park, Ki-Cheong Cheong, Jae-Ho 2025-11-21T02:37:02Z 2025-11-21T02:37:02Z 2025-11-11 2025-12 0006-2952 https://pubs.kist.re.kr/handle/201004/153602 Refractory hepatocellular carcinoma (HCC) perpetuates metastasis or recurrence through anti-cancer drug resistance, necessitating more effective and reliable therapeutic strategies. We propose a new therapeutic approach involving the discovery of novel small molecules through target identification and validation in a patient-derived metastatic HCC model. We showed that calcium/calmodulin-dependent protein kinase 2 alpha (CaMK2 alpha)-mediated enhancement of sarco/endoplasmic reticulum (ER) calcium ATPase 1 (SERCA1) expression level was pivotal events under anti-cancer drug treated conditions in patient-derived metastatic HCC cells. Increased SERCA1 was regulates to overloaded free calcium. SERCA is widely recognized as a key regulator of cytosolic free calcium under severe ER stress conditions. Though a cardiac dysfunction was unavoidable in vivo because of non-specific inhibition of SERCA isoforms by standard SERCA inhibitors. Based on the molecular structure of SERCA1, we discovered and synthesized two SERCA1-specific inhibitors, candidate 56 and 62. These compounds significantly reduced tumor size in the metastatic HCC xenograft tumor model without cardiac contractile dysfunction. This study first showed survival mechanism of patient-derived metastatic HCC cell, and propose a new therapeutic approach by the new small molecules, candidate 56 and 62, which are SERCA1 isoform-specific inhibitors without cardiac dysfunction by SERCA1 selectively inhibition. English Elsevier BV Discovery of SERCA1-specific small molecule inhibitors based on survival mechanisms in metastatic hepatocellular carcinoma cells that depend on CaMK2α-mediated SERCA1 expression Article 10.1016/j.bcp.2025.117424 1 Biochemical Pharmacology, v.242, no.Part 4 Biochemical Pharmacology 242 Part 4 Y scie scopus 001599858400001 2-s2.0-105018686821 Pharmacology & Pharmacy Pharmacology & Pharmacy Article CALCIUM MITOCHONDRIAL HOMEOSTASIS APOPTOSIS SIGNALS HISAT Patient-derived metastatic HCC Sarcoplasmic Endoplasmic reticulum calcium ATPase Calcium Calmodulin-dependent protein kinase 2 alpha