A chlorophyll precursor is a potent and specific inhibitor of cardiac sodium channels and displays anti-cancer properties

The human voltage-gated sodium channel hNa_V1.5 is essential for cardiac excitability, but this channel is also expressed in multiple cancers, promoting cell migration and malignancy. Here we identify Mg²⁺-protoporphyrin IX (MgPpIX), a Mg-containing tetrapyrrole and intermediate in chlorophyll biosynthesis, as a potent inhibitor of hNa_V1.5. The activity profile of various metal protoporphyrins correlates with the electrostatic potential at the metal center of the compounds. MgPpIX is specific to hNa_V1.5, as no inhibition of other hNa_V isoforms was detected. A mutagenesis study and structural modeling reveals that MgPpIX stabilizes the domain-II voltage sensor in the deactivated conformation. MgPpIX also inhibits native Na_V channels in breast cancer MDA-MB-231 and colorectal carcinoma SW480 cell lines, and suppresses cell migration. MgPpIX is an exceptionally potent and specific inhibitor of hNa_V1.5 and may serve as a lead compound in anti-cancer drug development.