Diacylglycerol acyltransferases 2 (DGAT2) catalyze the final step in the synthesis of triacylglycerol (TAG) from diacylglycerol (DAG). DGAT2 is a major target of interest for multiple diseases as the accumulation of TAGs has been functionally related to nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and coronary artery disease, and inhibition of DGAT2 is related to the enhancement of breast cancer cell radiosensitivity to potentially improve the radiotherapy effectiveness. Therefore, DGAT2 inhibition has been employed as a potential therapeutic strategy. Although several DGAT2 inhibitors have been reported, primarily based on a substituted imidazopyridine ring scaffold, the pharmacodynamic (PD) efficacy of inhibitors can be limited and dependent on the synthesis rate of the target. Proteolysis targeting chimeras (PROTACs) are heterobifunctional small-molecules that can promote the rapid and selective proteasome-mediated degradation of intracellular proteins through the recruitment of E3 ligase complexes and have the potential to deliver PD efficacy beyond detectable pharmacokinetics of PROTACs. Here, we developed several DGAT2 PROTACs with different linkers using analogs of DGAT2 inhibitors. The choice of linkers was guided by computational modeling and target degradation was validated by western blots and flow cytometry experiments. Given that the inhibitor binds to the target non-covalently, PROTACs can act catalytically and result in greater efficacy in combating several diseases.

Design and synthesis of DGAT2 PROTACs

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