DS18561882 is a potent and selective inhibitor of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) with IC50 of 0.0063 μM. The IC50 of DS18561882 for inhibiting MTHFD1 is 0.57 μM. DS18561882 has good oral pharmacokinetic properties.

Physicochemical Properties

Molecular Formula	C28H31F3N4O6S
Molecular Weight	608.629156351089
Exact Mass	608.191
CAS #	2227149-22-4
Related CAS #	2227149-22-4;
PubChem CID	139486677
Appearance	White to yellow solid powder
LogP	3.3
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	12
Rotatable Bond Count	5
Heavy Atom Count	42
Complexity	1190
Defined Atom Stereocenter Count	1
SMILES	S(C)(NC1C=CC(=CC=1OC(F)(F)F)C(N1CC2C(=O)OC3C(=CC=C(C=3C)N3CCN(C)[C@@H](C)C3)C=2CC1)=O)(=O)=O
InChi Key	OQKAKSSZSQPTDZ-INIZCTEOSA-N
InChi Code	InChI=1S/C28H31F3N4O6S/c1-16-14-34(12-11-33(16)3)23-8-6-20-19-9-10-35(15-21(19)27(37)40-25(20)17(23)2)26(36)18-5-7-22(32-42(4,38)39)24(13-18)41-28(29,30)31/h5-8,13,16,32H,9-12,14-15H2,1-4H3/t16-/m0/s1
Chemical Name	N-[4-[8-[(3S)-3,4-dimethylpiperazin-1-yl]-7-methyl-5-oxo-2,4-dihydro-1H-chromeno[3,4-c]pyridine-3-carbonyl]-2-(trifluoromethoxy)phenyl]methanesulfonamide
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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.
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	When tested against the MDA-MB-231 cell line, DS18561882 (0-150 nM) yields the lowest GI50 value (140 nM)[1].
ln Vivo	Oral treatment of DS18561882, at doses of 30, 100, or 300 mg/kg, twice daily, suppresses tumor growth inhibition in a dosage-dependent way. In mice, the dose of 300 mg/kg totally inhibits the tumor (TGI: 67%). With oral administration of 10, 30, 100, or 300 mg/kg, DS18561882, as well as its ACU (64.6, 264, 726 μg.h/ml), Cmax (11.4, 56.5, 90.1 μg /ml), and t1/2 (2.21, 2.16, 2.32 hours) for 30 mg/kg, 100 mg/kg, and 200 mg/kg, respectively, exhibit an excellent oral pharmacokinetic profile[1]. In this article[1], DS18561882, is suspended in a 0.5% (w/v) methyl cellulose 400 solution.
Animal Protocol	Animal/Disease Models: Five week old female BALB/cAJcl-nu/nu (nude) mice with MDA-MB-231 luc tumor cells (4 × 106 cells/mouse)[1] Doses: 30, 100 or 300 mg/kg Route of Administration: Oral administration; 30, 100 or 300 mg/kg; twice (two times) daily; until day 11 Experimental Results: Suppressed tumor growth in a dose-dependent manner.
References	[1]. Discovery of a Potent, Selective, and Orally Available MTHFD2 Inhibitor (DS18561882) with In Vivo Anti-Tumor Activity. J Med Chem. 2019 Oct 22.

Solubility Data

Solubility (In Vitro)

DMSO : ~150 mg/mL (~246.46 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 7.5 mg/mL (12.32 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 75.0 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: ≥ 7.5 mg/mL (12.32 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 75.0 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. Solubility in Formulation 3: ≥ 2.08 mg/mL (3.42 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. Solubility in Formulation 4: 20 mg/mL (32.86 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O 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	1.6430 mL	8.2152 mL	16.4303 mL
	5 mM	0.3286 mL	1.6430 mL	3.2861 mL
	10 mM	0.1643 mL	0.8215 mL	1.6430 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.