MTK458

MTK458 (MTK-458) is a potent, selective and brain penetrant PINK1 activator, MTK-458 promotes the first step in mitophagy. MTK458 selectively activates PINK1 by stimulating dimerization and stabilization of the PINK1/TOM complex. MTK458 binds to PINK1 and stabilizes an active heterocomplex, thereby increasing mitophagy. MTK458 reduces the PINK1 substrate pS65-Ubiquitin (pUb) in primary neurons and in vivo. MTK458 drives clearance of pathologic α-synuclein in vitro and in vivo, decreases pS129 α-synuclein aggregates and normalized both brain and corresponding plasma pUb levels in both cellular and animal models of α-synuclein aggregation (PD-like pathology).