MI-538 is an inhibitor (blocker/antagonist) of the interaction between menin and MLL fusion proteins; IC50 is 21 nM.

Physicochemical Properties

Molecular Formula	C27H25F3N8OS
Molecular Weight	566.60
Exact Mass	566.182
CAS #	1857417-10-7
PubChem CID	117636625
Appearance	White to off-white solid powder
LogP	5
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	11
Rotatable Bond Count	7
Heavy Atom Count	40
Complexity	914
Defined Atom Stereocenter Count	0
SMILES	N1(CC2=CNN=C2)C2=C(C=C(CN3CCC(NC4N=CN=C5SC(CC(F)(F)F)=CC5=4)CC3)C(O)=C2)C=C1C#N
InChi Key	QXLJOBRSTCFLMC-UHFFFAOYSA-N
InChi Code	InChI=1S/C27H25F3N8OS/c28-27(29,30)9-21-7-22-25(32-15-33-26(22)40-21)36-19-1-3-37(4-2-19)14-18-5-17-6-20(10-31)38(23(17)8-24(18)39)13-16-11-34-35-12-16/h5-8,11-12,15,19,39H,1-4,9,13-14H2,(H,34,35)(H,32,33,36)
Chemical Name	6-hydroxy-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]indole-2-carbonitrile
Synonyms	MI538; MI 538; MI-538
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ln Vitro	At a GI50 of 83 nM, MI-538 suppresses the growth of MLL leukemia cells. MI-538 demonstrated strong selectivity for MLL fusion protein-transformed cells, as evidenced by its lack of effect (up to 6 μM) on the development of control cell lines HL-60 and HM-2 lacking MLL translocation. MI-538 exhibits a modest nanomolar affinity (Kd=6.5 nM) for menin. greater binding affinity to menin and potentially greater permeability of the cell membrane are the causes of its strong cellular activity. Hoxa9 and Meis1 gene expression were significantly downregulated after receiving MI-538 therapy. In MLL-AF9 cells, Hoxa9 expression may be reduced by roughly 50% at a concentration of 100 nM 27, and the impact on Meis1 expression is more pronounced [1].
ln Vivo	MI-538 therapy led to a notable 80% reduction in MV4;11 tumor volume with less than 10% weight loss. The results of MI-538 showed a considerable improvement in minimum clearance, Cmax (maximum compound concentration) in plasma, and exposure (area under the curve, AUC, value). MI-538 has a half-life of about 1.6 hours. Moreover, MI-538 has a high oral bioavailability of around 50% [1].
References	[1]. Property Focused Structure-Based Optimization of Small Molecule Inhibitors of the Protein-Protein Interaction between Menin and Mixed Lineage Leukemia (MLL). J Med Chem. 2016 Feb 11;59(3):892-913.

Solubility Data

Solubility (In Vitro)

DMSO : ~100 mg/mL (~176.49 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 10 mg/mL (17.65 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 100.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 10 mg/mL (17.65 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 100.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 3: 2.08 mg/mL (3.67 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.7649 mL	8.8246 mL	17.6491 mL
	5 mM	0.3530 mL	1.7649 mL	3.5298 mL
	10 mM	0.1765 mL	0.8825 mL	1.7649 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.