Pharmacokinetics, Tissue Distribution, and Formulation Study of a Small-molecule Inhibitor of MKLP2, LG157

LG157 is a recently identified small-molecule inhibitor of mitotic kinesin-like protein 2 (MKLP2), an overlooked oncology target. This study aims to explore the drug developability of LG157, by assessing its druglike properties, determining plasma drug exposure in various oral formulations, and exploring the self-emulsifying drug delivery system (SEDDS). Solubility of LG157 ranges from 175 to 228 M across pH 1.0 to 13.0, with a LogD of 2.41 at pH 7.4. It showed a high protein binding rate of 92.58% in mouse plasma and 90.30% in human serum. The bioavailability radar plot aligns with experimental data (69-85%), indicating good bioavailability. In line with the computation prediction, preclinical formulation studies in mice reveal that all five formulations tested offer decent plasma LG157 exposure, with the highest level of LG157 exposure in the PEG300-based formulation. Subsequent tissue distribution studies in rats indicated that the compound is widely distributed with the highest concentration of LG157 in the liver and the lowest level in the brain. The optimal SEDDS formulation, SEDDS-F14, consists of 65% Oleic acid, 26.25% Tween 20, and 8.75% PEG400 as oil, surfactant, and co-surfactant, respectively. SEDDS optimization, based on the central composite design, has achieved the maximum loading of 188.7 mg/mL for LG157. These findings support the developability of LG157 and encourage continued exploration and refinement of formulations for improved therapeutic efficacy. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/573327v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@11b4bb7org.highwire.dtl.DTLVardef@107e320org.highwire.dtl.DTLVardef@d06f55org.highwire.dtl.DTLVardef@3d4854_HPS_FORMAT_FIGEXP M_FIG C_FIG