Description
MS67 is a potent and selective WD40 repeat domain protein 5 (WDR5) degrader with a K d of 63 nM. MS67 is inactive against other protein methyltransferases, kinases, GPCRs, ion channels, and transporters. MS67 shows potent acticancer effectsIn VitroMS67 (0.001-1 µM) induces WDR5 degradation at a concentration as low as 1 nM. MS67 induces WDR5 depletion much more effectively in all six mixed lineage leukemia (MLL)-r acute myeloid leukemia (AML) and four pancreatic ductal adenocarcinoma (PDAC) cell lines without a hook effect and in a concentration-dependent manner in PDAC cells. MS67 decreases H3K4me2/3 in both MV4;11 and MIA PaCa-2 cells, whereas other examined histone methylation marks such as H3K9me3, H3K27me3, and H3K36me3 are not affected. MS67 is effective in suppressing both WDR5-related gene expression programs and WDR5/MLL-induced H3K4 methylations on chromatin. The GI 50 values of MS67 in the two most sensitive AML lines, MV4;11 and EOL-1, are 15 nM and 38 nM, respectively. MLL-r acute leukemia cell lines including MV4;11, EOL-1, MOLM13, KOPN8, RS4;11, and THP-1 are sensitive to MS67, whereas leukemia cell lines that did not harbor MLL-r (including K562, HL60, and a murine AML line transformed by Hoxa9 plus Meis1) are insensitive to MS67. \nMS67 binds to VCB (VHL-Elongin C-Elongin B ternary complex), with a K d of 140 nM. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Western Blot AnalysisCell Line: MV4;11 cells Concentration: 0.001 µM, 0.005 µM, 0.01 µM, 0.05 µM, 0.1 µM, 0.5 µM, 1 µM Incubation Time: 18 hours Result: Induced WDR5 degradation at a concentration as low as 1 nM with DC 50 of 3.7 nM.In VivoMS67 (75 mg/kg; i.p.; twice daily; 5 days a week; for 20 days) significantly inhibits tumor growth in vivo and prolongs survival of the treated mice. After a single intraperitoneal (i.p.) injection of MS67 at a dose of 75 mg/kg, the Cmax reached at about 4.2 µM, and the concentration of MS67 retained above 0.5 µM over 12 hours. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: MV4;11 MLL-r AML xenograft mouse Dosage: 75 mg/kg Administration: i.p.; twice daily; 5 days a week; for 20 days Result: Inhibited tumor growth in vivo.Form:SolidIC50& Target:VHL WDR5 63 nM (Kd)