ETC-206 is a novel, potent and selective MNK1/2 inhibitor with IC50 of 64 nM for MNK1 and IC50 of 84 nM for MNK2. ETC-206 prevents BC-CML LSC self-renewal in vitro and boosts dasatinib antitumor activity in vivo when used in combination with the drug.

Physicochemical Properties

Molecular Formula	C25H20N4O2
Molecular Weight	408.45
Exact Mass	408.16
Elemental Analysis	C, 73.51; H, 4.94; N, 13.72; O, 7.83
CAS #	1464151-33-4
Related CAS #	1464151-33-4
PubChem CID	71766360
Appearance	Light yellow to yellow solid powder
LogP	3.9
Hydrogen Bond Donor Count	0
Hydrogen Bond Acceptor Count	4
Rotatable Bond Count	3
Heavy Atom Count	31
Complexity	668
Defined Atom Stereocenter Count	0
InChi Key	FWRFPHJSGLYXTD-UHFFFAOYSA-N
InChi Code	InChI=1S/C25H20N4O2/c26-15-18-1-3-20(4-2-18)23-16-27-24-10-9-22(17-29(23)24)19-5-7-21(8-6-19)25(30)28-11-13-31-14-12-28/h1-10,16-17H,11-14H2
Chemical Name	4-[6-[4-(morpholine-4-carbonyl)phenyl]imidazo[1,2-a]pyridin-3-yl]benzonitrile
Synonyms	Tinodasertib; ETC-206; ETC 206; ETC206
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

Targets	MNK1 (IC50 = 64 nM); MNK2 (IC50 = 86 nM)
ln Vitro	In the HeLa cell line, tinodasertib (ETC-206) inhibits eIF4E phosphorylation with an IC50 of 321 nM. The CellTiter-Glo viability assay was used in vitro to assess the anti-stress effects of ETC-206 against 25 blood cell lines, including the K562 cell line that overexpresses cardiovascular eIF4E (K562 o/ e eIF4E). for Ramos.2G6.4C10, AHH-1, MC 116, P3HR-1, DOHH2, MPC-11, SU-DHL-6, GK-5, and K562 o/e eIF4E cells [1].
ln Vivo	Next, using the K562 e/o eIF4E mouse xenograft model, the antitumor effects of ETC-206 were assessed. The drug was administered lateralized at 25, 50, or 100 mg/kg either by itself or in combination with a fixed dose of dasatinib at 2.5 mg/kg for the duration of the study. following the union. A dose of 2.5 mg/kg of dasatinib resulted in 88% tumor growth inhibition (TGI). Conversely, at the highest dose of 100 mg/kg, ETC-206 produced only 23 % of the maximum TGI, which was comparable to untreated animals and did not inhibit tumor growth. More significantly, 2, 5 of the 8 animals at 25, 50, and 100 mg/kg and 8 were tumor-free when ETC-206 and dasatinib at 2.5 mg/kg were combined. This increased tumor growth inhibition in a dose-dependent manner. kilograms, in that order. At all tested doses, the combination of dasatinib and ETC-206 inhibited tumor growth; no weight loss was observed. In syngeneic mouse xenograft models, the combination of dasatinib and ETC-206, as well as dual MNK1/2 and BCR-ABL1, inhibited tumor growth. The terminal elimination half-life of ETC-206 is regulated and is 1.77 hours for mice given 5 mg/kg po and t1/2=1.7 hours for mice given 1 mg/kg iv[1].
Cell Assay	ETC-206's ability to inhibit cell proliferation in 25 hematological cancer cell lines, including the K562 cell line that overexpresses eIF4E (K562 o/e eIF4E), is tested in vitro using the CellTiter-Glo viability assay. Generally speaking, the IC50 values fall into the micromolar range[1].
Animal Protocol	Mice: CD-1 female mice (6-8 weeks old) are weighed, and those selected for dosing are 24±2 g. Each group of three mice is chosen at random. ETC-206 is given to mice as a single injection into a tail vein at a dose of 1 mg/kg or as a single oral gavage at a dose of 5 mg/kg. 4 mL/kg and 8 mL/kg, respectively, are the injection volumes for intravenous (i.v.) and oral (p.o.) administration[1].
References	[1]. Optimization of Selective Mitogen-Activated Protein Kinase Interacting Kinases 1 and 2 Inhibitors for the Treatment of Blast Crisis Leukemia. J Med Chem. 2018 May 24;61(10):4348-4369.
Additional Infomation	Tinodasertib is a selective mitogen-activated protein kinase (MAPK)-interacting protein kinase (MNK) types 1/2 inhibitor with potential antineoplastic activity. Upon administration, tinodasertib may inhibit MNK1/2-dependent phosphorylation of eukaryotic initiation factor 4E (eIF4E) and interfere with its role in mRNA translation. eIF4E is an oncoprotein that must be phosphorylated before it can promote the proliferation and progression of tumor cells. MNKs are a family of serine/threonine kinases that have been implicated in oncogenic transformation and tumor progression.

Solubility Data

Solubility (In Vitro)

DMSO: ~82 mg/mL (~200.8 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 5 mg/mL (12.24 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 50.0 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: ≥ 5 mg/mL (12.24 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 50.0 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: ≥ 5 mg/mL (12.24 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 50.0 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	2.4483 mL	12.2414 mL	24.4828 mL
	5 mM	0.4897 mL	2.4483 mL	4.8966 mL
	10 mM	0.2448 mL	1.2241 mL	2.4483 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.