Taladegib (formerly LY2940680, LY 2940680, LY-2940680) is a potent and orally bioavailable Hedgehog pathway antagonist of the smoothened receptor being developed by Eli Lilly for the treatment of cancer. It blocks the Hedgehog (Hh) signaling pathway by attaching to the Smoothened (Smo) receptor. Taladegib possesses the potential to be applied to cancer patients who are vismodegib-resistant..

Physicochemical Properties

Molecular Formula	C26H24F4N6O
Molecular Weight	512.5
Exact Mass	512.194
Elemental Analysis	C, 60.93; H, 4.72; F, 14.83; N, 16.40; O, 3.12
CAS #	1258861-20-9
Related CAS #	1258861-20-9; 1258861-21-0 (HCl)
PubChem CID	49848070
Appearance	White solid powder
Density	1.4±0.1 g/cm3
Boiling Point	703.5±60.0 °C at 760 mmHg
Flash Point	379.3±32.9 °C
Vapour Pressure	0.0±2.2 mmHg at 25°C
Index of Refraction	1.634
LogP	2.7
Hydrogen Bond Donor Count	0
Hydrogen Bond Acceptor Count	9
Rotatable Bond Count	4
Heavy Atom Count	37
Complexity	794
Defined Atom Stereocenter Count	0
SMILES	CN1N=CC=C1C2=C3C(C=CC=C3)=C(N=N2)N4CCC(CC4)N(C)C(C5=C(C=C(C=C5)F)C(F)(F)F)=O
InChi Key	SZBGQDXLNMELTB-UHFFFAOYSA-N
InChi Code	InChI=1S/C26H24F4N6O/c1-34(25(37)20-8-7-16(27)15-21(20)26(28,29)30)17-10-13-36(14-11-17)24-19-6-4-3-5-18(19)23(32-33-24)22-9-12-31-35(22)2/h3-9,12,15,17H,10-11,13-14H2,1-2H3
Chemical Name	4-fluoro-N-methyl-N-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-yl]-2-(trifluoromethyl)benzamide
Synonyms	LY2940680; LY 2940680; LY-2940680
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	Smoothened
ln Vitro	In vitro activity: LY2940680 prevents the growth of cancer in cell lines with a mutation in the gene encoding smoothened that scientists had seen in cancer patients who became resistant to vismodegib in the past.[1]
ln Vivo	LY2940680 possesses superior pharmacokinetic qualities in both rodent and non-rodent species. When given orally to Ptch+/-p53-/-transgenic mice that spontaneously develop medulloblastoma, LY2940680 exhibits remarkable efficacy and significantly increases the mice's survival rate. Via magnetic resonance imaging of these mice, LY2940680 demonstrates the quick kinetics of anti-tumor activity. Additionally, immunohistochemistry analysis of medulloblastoma tumors shows that LY2940680 induces Caspase-3 activity and decreases proliferation. In the subcutaneous xenograft tumor stroma, LY2940680 inhibits Hh regulated gene expression and exhibits strong anti-tumor activity.[2]
Animal Protocol	Oral Mice
References	[1]. Expert Opin Investig Drugs . 2011 Dec;20(12):1649-64. [2]. Cancer Research, 2011, Volume 71, Issue 8, Supplement1
Additional Infomation	Taladegib has been used in trials studying the treatment of Solid Tumor, COLON CANCER, BREAST CANCER, Advanced Cancer, and Rhabdomyosarcoma, among others. Taladegib is an orally bioavailable small molecule antagonist of the Hedgehog (Hh)-ligand cell surface receptor smoothened (Smo) with potential antineoplastic activity. Taladegib inhibits signaling that is mediated by the Hh pathway protein Smo, which may result in a suppression of the Hh signaling pathway and may lead to the inhibition of the proliferation of tumor cells in which this pathway is abnormally activated. The Hh signaling pathway plays an important role in cellular growth, differentiation and repair; constitutive activation of this pathway is associated with uncontrolled cellular proliferation and has been observed in a variety of cancers.

Solubility Data

Solubility (In Vitro)

DMSO: 5~75 mg/mL (9.8~146.3 mM) Water: <1 mg/mL Ethanol: ~2 mg/mL (~3.9 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.88 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 (4.88 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 (4.88 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	1.9512 mL	9.7561 mL	19.5122 mL
	5 mM	0.3902 mL	1.9512 mL	3.9024 mL
	10 mM	0.1951 mL	0.9756 mL	1.9512 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.