MK-8245 is a liver-targeting SCD inhibitor for human SCD1 (IC50: 1 nM) and for rat/mouse SCD1 (IC50: 3 nM), with anti-diabetic and anti-dyslipidemic function.

SCD1 (rat):3 nM, SCD1 (human):1 nM, SCD1 (mouse):3 nM

In mice, rats, dogs, and cynomolgus monkeys, the primary site of action for MK-8245 (p.o.) is the liver, displaying minimal efficacy in tissues associated with potential adverse reactions. In eDIO mice, MK-8245 demonstrates a dose-dependent effect on glucose screening, enhancing glucose clearance (ED50: 7 mg/kg).

In experiments conducted on rat liver cells exhibiting functional activity of OATPs, MK-8245 demonstrated a potent inhibitory effect on SCD, with an IC50 of 68 nM. However, in experiments with HepG2 cells, which lack active OATPs, the compound was less effective, showing an IC50 of 1 μM. In HepG experiments, MK-8245 displayed high selectivity towards Δ-5 and Δ-6 desaturases. MK-8245 contains a tetrazole acetic acid group, endowing it with the capability for OATP recognition and liver-targeting functions.

High Throughput Screening: FITC-MBM1 at 15 nM and menin at 150 nM in the FP buffer are mixed and incubated for 1h in the dark at room temperature. For point screening, the 0.2 μL of each compound (20 μM final concentration, 1% DMSO) is added to 20 μL of the aliquot of the protein-peptide mixture and incubated on 384-well plates in the dark at room temperature for 1h. In confirmation screening, the serial dilution plates with compounds in DMSO are prepared and used to titrate the menin-FITC-MBM1 complex. Change in fluorescence polarization is monitored at 525 nm after excitations at 495 nm using the PHERAstar microplate reader (BMG) and applied to determine IC50 values with the Origin 7.0 program.