BMS-833923 (also known as XL139; BMS833923; XL-139; BMS 833923) is a novel, potent, selective, and orally bioavailable inhibitor of SMO (Smoothened) with potential antineoplastic activity. It inhibits the binding of BODIPY cyclopamine to SMO in a dose-dependent manner with an IC50 of 21 nM. BMS-833923 suppresses the sonic hedgehog (SHH) signaling pathway by inhibiting the SMO protein of the SHH pathway. Using a single oral dose, BMS-833923 effectively inhibits the activity of the HH pathway in xenograft models of pancreatic cancer and medulloblastoma.

Physicochemical Properties

Molecular Formula	C30H27N5O
Molecular Weight	473.57
Exact Mass	473.221
Elemental Analysis	C, 76.09; H, 5.75; N, 14.79; O, 3.38
CAS #	1059734-66-5
Related CAS #	1059734-66-5
PubChem CID	57662985
Appearance	White solid powder
Density	1.3±0.1 g/cm3
Index of Refraction	1.704
LogP	5.07
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	5
Rotatable Bond Count	7
Heavy Atom Count	36
Complexity	689
Defined Atom Stereocenter Count	0
SMILES	O=C(C1C([H])=C([H])C(=C([H])C=1[H])N([H])C1=NC2=C([H])C([H])=C([H])C([H])=C2C(C2C([H])=C([H])C([H])=C([H])C=2[H])=N1)N([H])C1C([H])=C(C([H])=C([H])C=1C([H])([H])[H])C([H])([H])N([H])C([H])([H])[H]
InChi Key	KLRRGBHZCJLIEL-UHFFFAOYSA-N
InChi Code	InChI=1S/C30H27N5O/c1-20-12-13-21(19-31-2)18-27(20)33-29(36)23-14-16-24(17-15-23)32-30-34-26-11-7-6-10-25(26)28(35-30)22-8-4-3-5-9-22/h3-18,31H,19H2,1-2H3,(H,33,36)(H,32,34,35)
Chemical Name	N-[2-methyl-5-(methylaminomethyl)phenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide
Synonyms	XL139; BMS833923; XL-139; BMS-833923; BMS 833923; XL 139
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: BMS-833923 inhibits the activity of the hedgehog pathway, lowers cell proliferation, and uses the intrinsic pathway to cause apoptosis in esophageal adenocarcinoma (EAC) cell lines. In [2] In vitro transcription of the canonical and prostate hedgehog signature genes is dose-dependently impacted by BMS-833923.[3]
ln Vivo	BMS-833923 administered as a single oral dose demonstrated a strong inhibition of the Hh pathway in animal models containing xenografts of pancreatic cancer and medulloblastoma. BMS-833923, administered at a dose of 10 mg/kg/day, significantly reduced the development of Barrett esophagus and esophageal adenocarcinoma in a rat model of gastroesophageal reflux disease by 35.7%.
Enzyme Assay	BMS-833923 (also known as XL-139) is a potentially antineoplastic small-molecule inhibitor that can be taken orally. Its IC50 is 21 nM, and it inhibits BODIPY cyclopamine binding to SMO in a dose-dependent manner.
Cell Assay	BMS-833923 suppressed the expression of GLI1 and PTCH1 in cell lines that expressed activated mutant SMO or wild-type SMO, with IC50 values ranging from 6 to 35 nM. It does-dependently inhibit cyclopamine binding to SMO in the FACS-based binding assays, with an IC50 value of 21 nM. With IC50 values of 10 μM, BMS-833923 treatment markedly decreased cell proliferation in the esophageal adenocarcinoma cell lines OE19 and OE33. In addition, BMS-833923 was discovered to suppress the percentage of ALDH+ cancer stem cells as well as the proliferation of multiple myeloma cells. Numerous additional tumor cells grown from patients with hematological malignancies, such as ALL, AML, and CM, were also inhibited in growth by it.
Animal Protocol	10 mg/kg/day; oral Animal models with medulloblastoma and pancreatic carcinoma xenografts
References	[1]. Semin Cutan Med Surg . 2011 Dec;30(4 Suppl):S14-8. [2]. Cancer Invest . 2013 Aug;31(7):480-9. [3]. Prostate . 2013 Dec;73(16):1810-23.
Additional Infomation	Smoothened Antagonist BMS-833923 is an orally bioavailable small molecule SMO (Smoothened) inhibitor with potential antineoplastic activity. SMO inhibitor BMS-833923 inhibits the sonic hedgehog (SHH) pathway protein SMO, which may result in a suppression of the SHH signaling pathway. SMO is a G-protein coupled receptor that lies just downstream of the SHH ligand cell surface receptor Patched-1 in the SHH pathway; in the absence of ligand Patched-1 inhibits SMO and ligand binding to Patched-1 results in increased levels of SMO. The SHH 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: 50~95 mg/mL (105.6~200.6 mM) Water: <1 mg/mL Ethanol: <1 mg/mL

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.28 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.1116 mL	10.5581 mL	21.1162 mL
	5 mM	0.4223 mL	2.1116 mL	4.2232 mL
	10 mM	0.2112 mL	1.0558 mL	2.1116 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.