ML216 is a potent inhibitor of the DNA unwinding activity of BLM helicase, showing similar IC50s of 3.0 and 0.97 μM for full length BLM and BLM636–1298 respectively.
ML216 (CID-49852229) acts as a powerful, selective, and cell-penetrable blocker of BLM helicase's DNA unwinding function, exhibiting IC50 values of 2.98 μM for BLM full-length and 0.97 μM for BLM636-1298. Additionally, ML216 suppresses BLM's ssDNA-dependent ATPase activity with a Ki of 1.76 µM, displaying antitumor activity[1][2].
体内研究
While ML216 similarly inhibits the unwinding activity of the related BLM and WRN helicases in vitro, its biological effects in human cells predominantly rely on BLM, indicating a BLM-specific mechanism of action in vivo. An elucidating co-crystal structure of BLM bound to the inhibitor would be revealing. It's suggested that cellular conditions in vivo may prompt a WRN conformation resistant to ML216[2].
体外研究
ML216 treatment (12.5-50 μM; 24-72 hours; PSNG5 and PSNG13 cells) reduces PSNF5 cell proliferation in a dose-dependent fashion, yet does not affect PSNG13 cells[1].
ML216 treatment results in a significant rise in the frequency of sister chromatid exchanges (SCEs) in PSNF5 cells, without affecting PSNG13 cells[1].
ML216 enhances the susceptibility of PSNF5 cells to aphidicolin while having no sensitizing impact on the BLM-lacking isogenic PSNG13 cells[1].
ML216 suppresses both the full-length WRN (IC50 of 5 μM) and the truncated WRN500-946 (IC50 of 12.6 μM), with the former showing 2.5 times greater sensitivity to ML216's inhibitory effect. Compared to WRN, BLM exhibits slightly higher sensitivity to ML216 inhibition (1.7 times based on IC50 values). Although ML216 effectively inhibits WRN, it predominantly targets BLM in human cells. ML216 equally inhibits the proliferation of both WRN+ and WRN-deficient cells and likewise increases their sensitivity to aphidicolin[1].
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