TargetValue BLM 636-1298 (Cell-free assay) 0.97 μM BLM full-length (Cell-free assay) 2.98 μM

Although ML216 inhibits unwinding by the sequence-related BLM and WRN helicases similarly in vitro, the apparent dependence on BLM for ML216 to exert its biological effects in human cells suggests BLM specificity for the drug’s mechanism of action in vivo. A co-crystal structure of BLM in complex with inhibitor would be informative. Cellular cues in vivo may induce a specific conformation of WRN that makes it resistant to ML216.

ML216 (12.5-50 µM; 24-72 hours; PSNG5 and PSNG13cells) treatment inhibits the proliferation of PSNF5 cells in a concentration-dependent manner, but not of PSNG13 cells. ML216 treatment leads to a statistically significant increase in the frequency of sister chromatid exchanges (SCEs) in PSNF5 cells, but not in PSNG13 cells. ML216 increases the sensitivity of PSNF5 cells to aphidicolin but has no sensitizing effect on isogenic PSNG13 cells devoid of BLM. ML216 inhibits both the full length WRN ( IC 50 of 5 μM) and a truncated WRN 500-946 ( IC 50 of 12.6 μM), with the former being 2.5-fold more sensitive to inhibition. BLM is a little more sensitive than WRN to inhibition by ML216 (1.7-fold based on IC 50 values). Despite the detectable inhibition of WRN by ML216, this compound appears selective for BLM in human cells. ML216 inhibits proliferation of WRN + and WRN − cells equally well, and similarly sensitized both cell types to aphidicolin. Cell Proliferation Assay Cell Line: PSNG5 and PSNG13cells Concentration: 12.5 μM or 50 µM Incubation Time: 24 hours, 48 hours, 72 hours Result: Inhibited the proliferation of PSNF5 cells, but not of PSNG13 cells, and did so in a concentration-dependent manner.

ML216 (CID-49852229)是一种有效地、选择性地、具有抗肿瘤活性的 DNA unwinding activity of BLM(Bloom’s syndrome protein) 的抑制剂。ML216 抑制解旋酶BLM636-1298和BLMfull-length的IC50值分别为0.97 μM和2.98 μM。