Simurosertib (formerly known as TAK-931) is a novel, selective and orally bioavailable cycle 7 (CDC7, cell division cycle 7-related protein) kinase inhibitor with anticancer activity. It has an IC50<0.3 nM for inhibiting CDC7. Due to its ability to bind to and inhibit CDC7, which stops DNA replication from starting during mitosis and ultimately results in cell cycle arrest and apoptosis, TAK-931 may have antineoplastic potential. This stops the proliferation of tumor cells that overexpress CDC7. The cell division cycle protein CDC7, a serine/threonine kinase, is overexpressed in many types of cancer and is essential for controlling the advancement of the cell cycle and triggering DNA replication.

Physicochemical Properties

Molecular Formula	C17H19N5OS
Molecular Weight	341.430661439896
Exact Mass	341.131
Elemental Analysis	C, 59.80; H, 5.61; N, 20.51; O, 4.69; S, 9.39
CAS #	1330782-76-7
Related CAS #	2135874-50-7 (hemihydrate);1330782-76-7;
PubChem CID	135564531
Appearance	White to off-white solid powder
Density	1.7±0.1 g/cm3
Index of Refraction	1.870
LogP	1.76
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	5
Rotatable Bond Count	2
Heavy Atom Count	24
Complexity	561
Defined Atom Stereocenter Count	1
SMILES	S1C(C2C=NNC=2C)=CC2=C1C(NC([C@@H]1CC3CCN1CC3)=N2)=O
InChi Key	XGVXKJKTISMIOW-ZDUSSCGKSA-N
InChi Code	InChI=1S/C17H19N5OS/c1-9-11(8-18-21-9)14-7-12-15(24-14)17(23)20-16(19-12)13-6-10-2-4-22(13)5-3-10/h7-8,10,13H,2-6H2,1H3,(H,18,21)(H,19,20,23)/t13-/m0/s1
Chemical Name	2-[(2S)-1-azabicyclo[2.2.2]octan-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)-3H-thieno[3,2-d]pyrimidin-4-one
Synonyms	TAK931; TAK-931; TAK 931; Simurosertib
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	Cdc7 (IC50 <0.3 nM)
ln Vitro	TAK-931 effectively suppresses CDC7 kinase activity (IC50<0.3 308). The selectivity of TAK-931 for CDC7 kinase inhibition is 120 times greater than that of other kinase inhibitors. The studies using kinases reveal this selectivity. The kinetics are time-dependent, atp-competitive, and pocket-based. In a dose-dependent manner, TAK-931 treatment inhibits cellular MCM2 phosphorylation at Ser40 (pMCM2), which delays the progression of the S phase and activates the DNA-damage checkpoint and caspase-3/7[1].
ln Vivo	Oral TAK-931 administration inhibits the xenografted COLO205's pMCM2 in a dose- and time-dependent manner in the COLO205-xenograft mouse model. In addition, TAK-931 shows notable antitumor activity in a number of xenograft models[1].
References	[1]. A novel CDC7-selective inhibitor TAK-931 with potent antitumor activity. European Journal of Cancer , 2016 , 69 (1) :S34.
Additional Infomation	Simurosertib is under investigation in clinical trial NCT03261947 (A Study to Evaluate the Safety, Tolerability, and Activity of TAK-931 in Participants With Metastatic Pancreatic Cancer, Metastatic Colorectal Cancer, and Other Advanced Solid Tumors). Simurosertib is an orally bioavailable inhibitor of cell division cycle 7 (cell division cycle 7-related protein kinase; CDC7), with potential antineoplastic activity. Upon administration, simurosertib binds to and inhibits CDC7; this prevents the initiation of DNA replication during mitosis, which causes cell cycle arrest and induces apoptosis. This inhibits cell growth in CDC7-overexpressing tumor cells. CDC7, a serine/threonine kinase and cell division cycle protein, is overexpressed in a variety of cancers and plays a key role in the activation of DNA replication and the regulation of cell cycle progression.

Solubility Data

Solubility (In Vitro)

DMSO: 68~75 mg/mL (199.2~219.7 mM) Ethanol: ~4 mg/mL (~11.7 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.32 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 25.0 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: ≥ 2.5 mg/mL (7.32 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 25.0 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: ≥ 2.5 mg/mL (7.32 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 25.0 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	2.9289 mL	14.6443 mL	29.2886 mL
	5 mM	0.5858 mL	2.9289 mL	5.8577 mL
	10 mM	0.2929 mL	1.4644 mL	2.9289 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.