Our Science
Restoring Metabolic Balance
The Role of the MPC in NASH
The mitochondrial pyruvate carrier (MPC) is a recently discovered protein complex in the inner mitochondrial membrane that mediates the rate of entry of pyruvate — an end product of carbohydrate metabolism and an important source of energy for the cell — into the mitochondria where subsequent oxidative metabolism occurs. The MPC is present in the mitochondria of cells in the body and orchestrates downstream signals that coordinate the cellular machinery, enzymatic pathways and gene expression with the nutritional state and energy need of the cell. In animal studies, liver-specific knockout of the MPC has been shown to protect against liver damage, including fibrosis, otherwise caused by overnutrition.
Modifications of the MPC affect downstream pathways that regulate many cell functions. For example, slowing the entry of pyruvate into the mitochondria results in an increase in the metabolism of amino acids such as alanine, aspartate and glutamate. Compounds such as MSDC-0602K that modulate the activity of the MPC can thus exert pleiotropic pharmacology in the context of overnutrition as described below.
Our Solution — MSDC-0602K
Our lead product candidate, MSDC-0602K, is a second-generation thiazolidinedione (TZD) designed to selectively bind to the MPC and modulate the entry of pyruvate into the mitochondria. The use of first generation TZDs, which are approved for the treatment of Type 2 diabetes, has been limited due to adverse effects eventually recognized to be caused by direct agonism of PPARγ, a mediator of gene transcription. While MSDC-0602K shares structural similarities with first generation TZDs, it was rationally designed to minimize direct agonism of PPARγ. We believe this approach has the potential to demonstrate the beneficial effects observed with first generation TZDs, but with an improved safety profile.
Preclinical studies suggest that modulation of the MPC mitigates the effects of overnutrition on NASH pathology, as well as insulin resistance with persistently elevated plasma insulin levels, and Type 2 diabetes. Overnutrition delivers excess pyruvate to the mitochondria through the MPC, driving changes in downstream metabolic pathways through a number of regulatory proteins. Preclinical studies have shown that treatment with MSDC-0602 mitigated the effects of overnutrition. We believe this effect is due to MSDC-0602’s impact on certain cellular functions and regulatory proteins, as illustrated in the figure below.
Mitigation of Key Effects of Overnutrition by MSDC-0602
By targeting the MPC we believe MSDC-0602K addresses the core pathology of NASH and insulin resistance, and at a point that is upstream from targets that are the focus of other NASH development programs. Given the numerous downstream pathways involved in the pathology of NASH, we believe that it is important to intervene upstream in order to produce a more comprehensive response to treatment.
Furthermore, by acting at the initial point of metabolic dysfunction, we believe this approach has the potential to have a dual impact on liver damage and insulin resistance, thus addressing the core pathologies of both NASH and Type 2 diabetes. Consequently, we believe MSDC-0602K has potential to be used as a cornerstone NASH therapy.
Cell Functions
| Key Factor | Description | Overnutrition vs. Normal Function | MSDC-0602 vs. Overnutrition |
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| Insulin Sensitivity | Cellular response to insulin |
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| de novo lipid synthesis | Making new fat |
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| Fatty acid oxidation | Burning fat |
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| Inflammation | Reaction to injury |
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Key Regulatory Proteins
| Key Factor | Description | Overnutrition vs. Normal Function | MSDC-0602 vs. Overnutrition |
|---|---|---|---|
| mTORC1 | Important nutrient sensor |
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| SREBP | Transcription factors regulating fat synthesis |
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| PPARγ, PPARα | Transciption factors regulating fat metabolism and inflammation |
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| HIF1α | Transcription factors responding to oxygen |
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