Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that facilitates the transfer of cholesteryl esters and triglycerides between the lipoproteins. CETP catalyzes the reciprocal neutral lipid exchange (cholesteryl ester and triglyceride) between HDL and apoB-containing lipoprotein particles, and as a result, plasma HDL cholesterol is reduced. Several common variants in CETP have been reported to be associated with variation in plasma lipid levels, CAD risk and/or CETP mass/activity. The rare genetic variants in the CETP gene also contribute to the phenotypic variation of HDL-C in the general population. CETP inhibitors targets the CETP enzyme to significantly increase serum HDL-C and decrease LDL-C levels. Inhibition of CETP is considered a potential approach to treat dyslipidemia.

Evacetrapib (also known as LY2484595) is a potent, selective and orally active CETP inhibitor.

Evacetrapib inhibits human recombinant CETP protein and CETP activity in human plasma with IC50 values of 5.5 nM and 36 nM, respectively. In double transgenic mice expressing human CETP and apoAI, Evacetrapib administered orally at 30 mg/kg resulted in 98.4%, 98.6%, and 18.4% inhibition of CETP activity at 4, 8 and 24 h post dose respectively. Moreover, Evacetrapib dosed orally at 30 mg/kg resulted in 129.7% increase in HDL-C 8 h after oral administration. Thus, Evacetrapib significant HDL-cholesterol elevation in an appropriate animal model. In addition, Evacetrapib has no blood pressure and aldosterone-inducing off-target activities. Besides, Evacetrapib suppresses colorectal cancer (CRC) cell growth and and induces cell apoptosis. Evacetrapib inhibits the Wnt/β-catenin signaling pathway and activating the JNK signaling pathway in CRC. Therefore, Evacetrapib displays an anti-colorectal cancer effect.

Collectively, Evacetrapib is a selective and orally active CETP inhibitor that can be used for cardiovascular disease and cancer research.

[1] Guoqing Cao, et al. J Lipid Res. 2011 Dec;52(12):2169-2176.
[2] Limei Hu, et al. Biol Pharm Bull. 2022;45(9):1238-1245.