CS-2239

PKL1

HMN-176 (2.5 μM) greatly increases the duration of mitosis in hTERT-RPE1 and CFPAC-1 Cell lines. The effect of HMN-176 on spindle morphology does not appear to be related to effects on microtubule polymerization. HMN-176 (2.5, 0.25, and 0.025 μM) inhibits aster formation in a concentration dependent manner. HMN-176 (0.1, 1.0, or 10.0 µg/mL) demonstrates inhibitory effects in multiple tumors, with notable activity seen in breast, nonsmall-cell lung, and ovarian cancer specimens. HMN-176 demonstrates activity towards 63% of the breast (5/8), 67% of the non-small cell lung (4/6), and 57% of the ovarian (4/7) tumor specimens treated with 10.0 µg/mL. HMN-176 shows potent cytotoxicity, with a mean IC ₅₀ value of 118 nM. HMN-176 displays similar cytotoxicity against tumors with various characteristics from different organs. Treatment with 3 μM HMN-176 suppresses the expression of MDR1 mRNA by 56%. HMN-176 has no significant effect on the residual promoter activity.

HMN-176 prevents spindle assembly and meiosis in Spisula oocytes by inhibiting centrosome-dependent MT nucleation, i.e., aster formation. Oocytes treated with 0.25 μM HMN-176 undergoes GVBD, but asters or spindles fails to form, even after prolonged periods. After p.o. of HMN-214 to male rats, the prodrug is not detected in the plasma, while plasma levels of HMN-176 peaks at 2 h and gradually decreases thereafter.