Identification of sinensetin as a selective inhibitor for mitogen-activated protein kinase kinase 6 and an anticancer agent for non-small cell lung cancer.

Natural compounds are an invaluable source for bioactive small molecules. Cellular activities modulated by them are generally achieved by binding specific cellular targets. However, identification of target(s) for a natural compound is challenging and a hurdle for further development of them as drugs. Sinensetin is derived from Schisandra sphenanthera and the major component of a traditional medicine. Although Sinensetin possesses pharmacological activities, including antioxidants, anti-inflammatory, and anticancer, the molecular mechanisms for its activities remain unclear due to lack of information for its target. In addition, the anticancer effects of sinensetin against non-small cell lung cancer (NSCLC) have not been studied. Here, we described sinensetin as a specific inhibitor of MKK6 with a KD value of 66.27 μM. Sinensetin inhibited the proliferation of NSCLC cells and lung patient-derived xenograft-derived organoids (LPDXO), and induced G1 phase cell-cycle arrest. Sinensetin attenuated the MAPK signaling pathway by directly inhibiting MKK6, but not MKK3. In silico molecular docking analysis indicated that sinensetin was specifically bound near the αG-helix of MKK6, but not MKK3. High MKK6 expression levels were observed in NSCLC patients. MKK6 knockout abolished the sinensetin-mediated inhibition of NSCLC cell proliferation. Taken together, sinensetin is a novel MKK6 inhibitor with therapeutic potential for NSCLC.