Small Molecules Targeting the Mitochondrial Permeability Transition

It is now clear that the mitochondrial permeability transition pore (mtPTP) plays a key role in a wide variety of human diseases whose common pathology is based in mitochondrial dysfunction. Despite the facts that robust assays for the activity of the mtPTP have been established and small molecules are of obvious therapeutic importance, the identification of small molecules specifically targeting the mtPTP has not advanced. Using resources within the NIH Molecular Libraries Probe Production Centers Network (MLPCN), a number of novel small molecules that serve as inhibitors of mtPTP activation were identified and optimized. One of these compounds, the probe compound ML404 (CID 72199308) inhibits mitochondrial swelling with an EC₅₀ = 4.9 nM, while it perturbs mitochondrial coupling (an undesired effect) at > 100 μM. This compound increases the calcium retention capacity (CRC) of mitochondria (a measure of mtPTP inhibition) 14.8-fold at 12.5 μM, a concentration that does not affect mitochondrial respiration at which the compound appears non-toxic. Compared to the prior art, the probe ML404 (CID 72199308) is the best-in-class inhibitor of the mtPTP. When the probe and analogues are used as recommended, they are “fit-for-purpose” and should be useful for advancing the search for small-molecule therapeutics for some of the most wide-spread and therapeutically challenging human diseases, such as, multiple sclerosis (MS), amyotropic lateral sclerosis (ALS), Alzheimer's disease (AD), muscular dystrophies (MDs), heart infarction, and stroke.