MI-538

Research use only, not for human use.

MI-538 is potent and selective menin–MLL interaction inhibitor (IC50=21 nM).

MI-538 is potent and selective menin–MLL interaction inhibitor (IC50=21 nM); shows the most potent binding affinity to menin (Kd = 6.5 nM) obtained for small molecule menin–MLL inhibitor reported to date; exhibits significantly increased activity, selectivity, polarity and pharmacokinetic profile over MI-136 and demonstrates a pronounced effect in a mouse model of MLL leukemia.

MI-538 inhibits the proliferation of MLL leukemia cells with a GI50 of 83 nM. MI-538 shows no effect (up to 6 μM) on growth of the control cell lines HL-60 and HM-2, which do not harbor MLL translocations, demonstrating good selectivity toward MLL fusion protein transformed cells. MI-538 binds to menin with low nanomolar affinity (Kd=6.5 nM). Its potent cellular activity originates from the improved binding affinity to menin and possibly increased cell membrane permeability. Treatment with MI-538 results in strong down regulation of expression of Hoxa9 and Meis1 genes. About 100 nM 27 was sufficient to reduce by ~50% Hoxa9 expression in MLL-AF9 cells, and even more pronounced effect was seen on Meis1 expression.

Treatment with MI-538 results in a pronounced, about 80%, reduction in the MV4;11 tumor volume, without causing substantial signs of toxicity reflected by less than 10% reduction of the body weight. MI-538 demonstrates markedly improved exposure (area under the curve, AUC, values), Cmax (maximum compound concentration) in the blood plasma, and the lowest value of clearance. The half-life of MI-538 is about 1.6 h. MI-538 has also high oral bioavailability (~50%).

MI538 | MI 538

Chromatin/Epigenetic

HMTase

HMTase

Cancer

——

1857417-10-7

566.6006

C27H25F3N8OS

>98% (HPLC)

DMSO; Need ultrasonic and warming

N#CC(N1CC2=CNN=C2)=CC3=C1C=C(O)C(CN4CCC(NC5=C(C=C(CC(F)(F)F)S6)C6=NC=N5)CC4)=C3

1H-Indole-2-carbonitrile, 6-hydroxy-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]-

(-20℃)

With Ice Pack

≥ 2 years