Abstract

OTS167 is a potent maternal embryonic leucine zipper kinase (MELK) inhibitor undergoing clinical testing as antineoplastic agent. We aimed to identify the UDP-glucuronosyltransferases (UGTs) involved in OTS167 metabolism, study the relationship between UGT genetic polymorphisms and hepatic OTS167 glucuronidation, and investigate the inhibitory potential of OTS167 on UGTs. Formation of a single OTS167-glucuronide (OTS167-G) was observed in pooled human liver (HLM) (K_m=3.4 ± 0.2 μM), intestinal microsomes (HIM) (K_m=1.7 ± 0.1 μM) and UGTs. UGT1A1 (64 μl/min/mg) and UGT1A8 (72 μl/min/mg) exhibited the highest intrinsic clearances (CL_int) for OTS167 followed by UGT1A3 (51 μl/min/mg) and UGT1A10 (47 μl/min/mg); UGT1A9 was a minor contributor. OTS167 glucuronidation in HLM was highly correlated with thyroxine glucuronidation (r=0.91, p<0.0001), SN-38 glucuronidation (r=0.79, p<0.0001) and UGT1A1 mRNA (r=0.72, p<0.0001). Nilotinib (UGT1A1 inhibitor) and emodin (UGT1A8 and UGT1A10 inhibitor) exhibited the highest inhibitory effects on OTS167-G formation in HLM (68%) and HIM (47%). We hypothesize that OTS167-G is an N-glucuronide according to mass spectrometry (MS). A significant association was found between rs6706232 and reduced OTS167-G formation (p=0.03). No or weak UGT inhibition (range: 0 - 21%) was observed using clinically relevant OTS167 concentrations (0.4 - 2 μM). We conclude that UGT1A1 and UGT1A3 are the main UGTs responsible for hepatic formation of OTS167-G. Intestinal UGT1A1, UGT1A8 and UGT1A10 may contribute to first-pass OTS167 metabolism after oral administration.