IPG8294: First-in-Class small molecule inhibitor targeting NADase to treat neurodegenerative diseases


Mitochondrial dysfunction plays a crucial role in the pathogenesis of various diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), Mitochondrial myopathy (MM), Duchenne muscular dystrophy (DMD) and other related disorders. The enzyme "Target," which possesses hydrolytic activity, has been identified as a significant contributor to the development of mitochondrial dysfunction in various pathological conditions. IPG8294 has been specifically designed to selectively target and suppress the hydrolytic activity of the aforementioned enzyme. Therefore, IPG8294 holds great potential as a therapeutic agent for effectively treating disorders associated with mitochondrial dysfunction.

Mechanism of Action


■ Mitochondrial quality control pathways are tightly regulated and interconnected, including mitochondrial fission and fusion, mitophagy, and mitochondrial biogenesis, 

■ Dysregulation of the target enzyme plays a substantial role in mitochondrial dysfunction.

■ Blockade of the target by IPG8294 holds the potential to restore mitochondrial function and improve the progression of associated diseases.

Key differentiation

■ IPG8294 represents a groundbreaking small-molecule inhibitor with significant potential in addressing mitochondrial dysfunction. 

■ IPG8294 exhibits a Disease-modifying effect.

■ IPG8294 is being developed as a therapeutic agent for the treatment of various neurodegenerative and mitochondrial diseases, encompassing AD, PD, HD, ALS, MM, and DMD. 

In vitro and in vivo properties

In vitro:

■Strong inhibition effect of target enzyme activity with IC50 = 6.5 nM.

In vivo:

■IPG8294 improves mitochondrial quality in APP/PS1 mice brains.


TEM: The percentage of damaged mitochondria (Type II, III, IV) was significantly decreased by IPG8294 treatment (Statistic data was expressed as mean ± SEM. **** P < 0.0001 vs. the vehicle group)

■IPG8294 increases expression of PSD-95 and Synaptophysin in a dose-dependent manner in APP/PS1 mice brain.


WB: Synapse loss was significantly prevented by IPG8294 treatment in APP/PS1 mice brain (Statistic data was expressed as mean ± SEM. *** P < 0.001, **** P < 0.0001 vs. the vehicle group)

■IPG8294 inhibits lactate acid increase in the muscle of a mitochondrial myopathy mouse model.


Lactic acidosis is a common feature of mitochondrial disease due to anaerobic glycolysis. The lactic acid levels in the gastrocnemius muscle of PUS1 KO mice after 30 minutes of treadmill running were significantly decreased with IPG8294 treatment (the statistical data were expressed as the mean ± SEM. * P < 0.05, ** P < 0.01 versus the vehicle group)


■Li et al, Discovery of a First-in-class CD38 Inhibitor for theTreatment of Mitochondrial Myopathy, J Med Chem (In press)