DGAT-1 Inhibitor

Hypertriglyceridemia, NASH

Overview & Profile

We are developing small molecule inhibitors, including VK1430, of the enzyme diacylglycerol O-acyltransferase 1 (DGAT-1) for the potential treatment of metabolic disorders such as hypertriglyceridemia, NASH, obesity, and dyslipidemia. This program is in the Preclinical stage.

DGAT-1 is a key enzyme involved in the formation of triglycerides and is highly expressed in human fat metabolism sites such as intestine, liver, and adipose. Dietary triglycerides cannot be absorbed directly in the gastrointestinal, or GI, tract and are broken down into free fatty acids and monoglycerol in the intestine by pancreatic lipase. Once absorbed, the free fatty acids and glycerol are reassembled into triglycerides at the site of absorption, called an enterocyte, and packaged into chylomicron particles to be transported in the lymphatic system to be used throughout the body. DGAT-1 is one of two enzymes that catalyze the steps of triglyceride biosynthesis from mono- or diacylglycerol and fatty acids, and is mainly distributed in the intestine, liver and adipose tissue.

DGAT-1 Mediates Absorption of Fats from the GI Tract


Dietary triglycerides (TGs) cannot be absorbed directly in GI tract

  • They are broken down into fatty acids and monoglycerol by pancreatic lipase

Once absorbed, fatty acids and glycerol are reassembled into TGs at site of absorption (enterocyte)

  • TGs are then packaged into chylomicron particles and transported throughout body

DGAT-1 null mice exhibit both reduced post-meal plasma triglyceride levels and increased energy expenditure but have normal levels of circulating free fatty acids. Conversely, transgenic mice that overexpress DGAT-1 in adipose tissue are predisposed to obesity when fed a high-fat diet and have elevated levels of circulating free fatty acids.

DGAT-1 is a potential therapeutic target for reduction of triglyceride levels in the circulation and fat accumulation in adipose tissues. However, non-selective systemic reduction of fat formation can lead to undesirable side effects demonstrated in DGAT-1 null mice. By introducing a unique chemical function group into the DGAT-1 inhibitors, Viking has developed a series of novel compounds with tissue- targeting properties intended to mitigate potential side effects by selectively targeting the enterocyte (or intestinal absorptive cells) in the intestine, to inhibit dietary triglyceride uptake, or the liver, to inhibit de novo triglyceride synthesis. The compounds have demonstrated efficacy in animal models of dietary induced obesity.