Ziftomenib (KO-539) is an orally bioactive inhibitor of the menin-MLL interaction with anti-tumor activity (WO2017161028A1, compound 151).

Physicochemical Properties

Molecular Formula	C33H42F3N9O2S2
Molecular Weight	717.870893955231
Exact Mass	717.285
CAS #	2134675-36-6
PubChem CID	138497449
Appearance	Light brown to brown solid powder
LogP	5.6
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	14
Rotatable Bond Count	10
Heavy Atom Count	49
Complexity	1270
Defined Atom Stereocenter Count	1
SMILES	S(C)(N1CCN(CC1)[C@@H](C)CN1C(C#N)=CC2C(C)=C(C=CC1=2)CN1CCC(CC1)NC1=C2C=C(CC(F)(F)F)SC2=NC(NC)=N1)(=O)=O
InChi Key	BGGALFIXXQOTPY-NRFANRHFSA-N
InChi Code	InChI=1S/C33H42F3N9O2S2/c1-21(43-11-13-44(14-12-43)49(4,46)47)19-45-25(18-37)15-27-22(2)23(5-6-29(27)45)20-42-9-7-24(8-10-42)39-30-28-16-26(17-33(34,35)36)48-31(28)41-32(38-3)40-30/h5-6,15-16,21,24H,7-14,17,19-20H2,1-4H3,(H2,38,39,40,41)/t21-/m0/s1
Chemical Name	4-methyl-5-[[4-[[2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]-1-[(2S)-2-(4-methylsulfonylpiperazin-1-yl)propyl]indole-2-carbonitrile
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	Histone methyltransferases such as the mixed-lineage leukemia (MLL) protein are essential for the epigenetic control of gene transcription. Chimeric MLL fusion proteins, which are the product of chromosomal translocations of the MLL gene located at chromosome 11, band q23 (11q23), are a characteristic shared by many acute leukemias, including acute myeloblastic leukemia (AML), acute lymphoblastic leukemia (ALL), and mixed-lineage leukemia (MLL). Leukemogenesis is ultimately caused by MLL fusion proteins, which lack the original histone methyltransferase activity of the MLL C-terminus and instead have the capacity to control the transcription of multiple oncogenes, such as HOX and MEIS1. This leads to increased cell proliferation and decreased cell differentiation[1].
References	[1]. Substituted inhibitors of menin-mll and methods of use. WO2017161028A1.
Additional Infomation	Ziftomenib is an orally bioavailable inhibitor of the menin-mixed lineage leukemia (MLL; myeloid/lymphoid leukemia; KMT2A) fusion protein, with potential antineoplastic activity. Upon oral administration, ziftomenib prevents the interaction between the two proteins menin and MLL, and thus the formation of the menin-MLL complex. This reduces the expression of downstream target genes and results in an inhibition of the proliferation of MLL-rearranged leukemic cells. The menin-MLL complex plays a key role in the survival, growth and proliferation of certain kinds of leukemia cells.

Solubility Data

Solubility (In Vitro)

DMSO : 100 mg/mL (139.30 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.08 mg/mL (2.90 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 20.8 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: ≥ 2.08 mg/mL (2.90 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.3930 mL	6.9650 mL	13.9301 mL
	5 mM	0.2786 mL	1.3930 mL	2.7860 mL
	10 mM	0.1393 mL	0.6965 mL	1.3930 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.