HMGR is an oncotarget of CRC.
JMF3086 targeting HMGR and HDACs is effective therapy in different preclinical CRC models.
JMF3086 down-regulated inflammatory, proliferation, stemness and anti-apoptotic genes but up-regulated tumor suppressor genes.
Addition of chemotherapeutic and molecular targeted agents stepwise prolongs the survival of metastatic colorectal cancer (CRC), implying the importance of new drugs discovery. Furthermore, combination therapy is a rational approach to improve the anti-cancer efficacy. Here, we demonstrate HMGR is a target for CRC and design a dual HMGR and HDAC inhibitor JMF3086. It inhibits tumor progression, metastasis and stemness in several preclinical models, conferring a significant benefit above lovastatin plus SAHA. JMF3086 also potentiates the effect of oxaliplatin, an important chemotherapeutic agent of CRC. These results provide a rationale for clinical studies of JMF3086 to advance the survival of metastatic CRC.