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Purity: ≥98%
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.
| Targets |
Smoothened
BMS-833923 (XL-139) specifically targets the Smoothened (SMO) receptor in the Hedgehog (Hh) signaling pathway (IC50 = 4.0 nM for human SMO; Ki = 2.1 nM) [2] BMS-833923 (XL-139) shows no significant inhibition of other GPCRs or kinases (IC50 > 10 μM for 300+ tested targets) [2] |
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| 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]
In recombinant human SMO activity assays, BMS-833923 (XL-139) dose-dependently inhibits Hh pathway activation with an IC50 of 4.0 nM and Ki of 2.1 nM, acting as a competitive SMO antagonist [2] - In Hh pathway-dependent cancer cell lines (basal cell carcinoma: ASZ001, UW-BCC1; prostate cancer: LNCaP, PC-3; medulloblastoma: DAOY), BMS-833923 (XL-139) exhibits antiproliferative activity with IC50 values ranging from 15 to 85 nM. After 72 hours of treatment, 100 nM concentration reduces cell viability by 60-80% across these lines [2][3] - In ASZ001 BCC cells, BMS-833923 (XL-139) (50 nM) downregulates Hh target genes Gli1 (82% reduction) and Ptch1 (75% reduction) at mRNA level after 24 hours, and reduces Gli1 protein levels by 78% [2] - In LNCaP prostate cancer cells, BMS-833923 (XL-139) (70 nM) induces G1 cell cycle arrest (G1 phase cells increased from 43% to 71% after 48 hours) and inhibits colony formation by 72% compared to control. It also downregulates Cyclin D1 and Bcl-2 protein expression (65% and 58% reduction, respectively) [3] - In DAOY medulloblastoma cells, BMS-833923 (XL-139) (60 nM) induces apoptosis, with Annexin V-positive cells increasing from 3% (control) to 38% after 72 hours, and caspase-3/7 activity elevated by 3.4-fold [2] - In normal human prostate stromal cells (PrSCs), BMS-833923 (XL-139) shows low toxicity at concentrations up to 500 nM (cell viability > 90% vs. control) [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%.
In nude mice bearing subcutaneous ASZ001 BCC xenografts, oral administration of BMS-833923 (XL-139) (30 mg/kg/day for 21 days) significantly inhibits tumor growth. Tumor volume was reduced by 75% compared to vehicle-treated mice, and Gli1 protein levels in tumors were downregulated by 73% [2] - In nude mice bearing subcutaneous LNCaP prostate cancer xenografts, oral BMS-833923 (XL-139) (40 mg/kg/day for 28 days) reduces tumor volume by 70% and tumor weight by 68% vs. vehicle controls. Tumor tissues show decreased Ki-67 (proliferation marker, 62% reduction) and increased cleaved caspase-3 expression [3] - In a Ptch1+/− transgenic mouse model of spontaneous BCC, oral BMS-833923 (XL-139) (25 mg/kg/day for 4 weeks) reduces tumor incidence from 82% to 15% and regresses existing tumors by 63% [2] |
| 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.
SMO binding assay: Recombinant human SMO protein was immobilized on a sensor chip, and BMS-833923 (XL-139) (0.01 nM-10 nM) was incubated with a fluorescently labeled SMO agonist in binding buffer (50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM DTT) at 25°C for 60 minutes. Fluorescence polarization was measured to quantify binding affinity, yielding a Ki of 2.1 nM [2] - Hh pathway reporter assay: NIH3T3 cells stably transfected with a Gli-responsive luciferase reporter plasmid were preincubated with Hh ligand (100 ng/mL) for 12 hours, then treated with BMS-833923 (XL-139) (0.01 nM-100 nM) for 24 hours. Luciferase activity was measured to assess pathway inhibition, with an IC50 of 4.0 nM [2] - Off-target selectivity assay: BMS-833923 (XL-139) (10 μM) was screened against a panel of 300+ kinases and GPCRs using enzymatic activity or radioligand binding assays. No significant off-target inhibition (>50% activity reduction) was observed [2] |
| 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.
Antiproliferation assay: Hh pathway-dependent cancer cell lines (ASZ001, UW-BCC1, LNCaP, PC-3, DAOY) and normal PrSCs were seeded in 96-well plates at 3×10³ cells/well and cultured for 24 hours. BMS-833923 (XL-139) was added at concentrations of 0.1-1000 nM, and cells were incubated for 72 hours. Cell viability was assessed by MTT assay, and IC50 values were derived [2][3] - Gene/protein expression assay: ASZ001 or LNCaP cells were seeded in 6-well plates at 2×10⁵ cells/well and treated with BMS-833923 (XL-139) (50-70 nM) for 24 hours. Total RNA was extracted for qPCR analysis of Gli1 and Ptch1 mRNA levels, and total protein was extracted for Western blot detection of Gli1, Cyclin D1, and Bcl-2 [2][3] - Cell cycle assay: LNCaP cells were treated with BMS-833923 (XL-139) (70 nM) for 48 hours. Cells were fixed, stained with propidium iodide, and analyzed by flow cytometry to determine cell cycle distribution [3] - Apoptosis assay: DAOY cells were treated with BMS-833923 (XL-139) (60 nM) for 72 hours. Apoptosis was quantified by Annexin V-FITC/PI staining, and caspase-3/7 activity was measured by luminescent assay [2] - Colony formation assay: LNCaP or ASZ001 cells were seeded in 6-well plates at 500 cells/well and treated with BMS-833923 (XL-139) (50-70 nM) or vehicle. After 14 days of culture, colonies were stained with crystal violet and counted to calculate inhibition rate [2][3] |
| Animal Protocol |
10 mg/kg/day; oral
Animal models with medulloblastoma and pancreatic carcinoma xenografts Nude mice (subcutaneous ASZ001 BCC xenograft model): 6-8 weeks old nude mice were subcutaneously inoculated with ASZ001 cells (5×10⁶ cells/mouse). When tumors reached ~100 mm³, mice were randomly divided into vehicle and BMS-833923 (XL-139) groups. BMS-833923 (XL-139) was suspended in 0.5% carboxymethylcellulose sodium and administered orally at 30 mg/kg/day for 21 days. Vehicle-treated mice received carboxymethylcellulose sodium. Tumor volume was measured every 3 days, and tumors were excised for Gli1 protein analysis [2] - Nude mice (subcutaneous LNCaP prostate cancer xenograft model): Mice were subcutaneously inoculated with LNCaP cells (5×10⁶ cells/mouse). When tumors reached ~120 mm³, mice were treated with oral BMS-833923 (XL-139) (40 mg/kg/day) or vehicle for 28 days. Tumor volume was measured every 3 days, and tumors were excised for Ki-67 immunostaining and cleaved caspase-3 Western blot [3] - Ptch1+/− transgenic mouse model: 6-week-old Ptch1+/− mice were administered oral BMS-833923 (XL-139) (25 mg/kg/day) or vehicle for 4 weeks. Tumor incidence and size were monitored weekly, and skin tumors were counted and measured at study end [2] |
| Toxicity/Toxicokinetics |
In vitro experiments showed that BMS-833923 (XL-139) had low cytotoxicity to normal human cells (PrSCs IC50 > 500 nM; dermal fibroblasts IC50 > 600 nM) [2][3] In vivo studies showed that at the test dose (25-40 mg/kg, orally), BMS-833923 (XL-139) caused mild weight loss in mice (≤7% vs. baseline), but no significant lethality or severe organ toxicity was observed [2][3] Compared with the vector control group, there were no significant changes in liver function (ALT, AST) or kidney function (creatinine, BUN) in mice treated with BMS-833923 (XL-139) [2][3] BMS-833923 The plasma protein binding rate (XL-139) was 97-99% in mice and 98-99% in humans (in vitro plasma binding assay) [2]
- Skin toxicity: In Ptch1+/− mice treated with 25 mg/kg/day for 4 weeks, 25% of the mice developed mild dry skin, but no hair loss or severe skin reactions were observed [2] |
| References | |
| Additional Infomation |
BMS-833923, a smoothed antagonist, is a small-molecule SMO (smoothed) inhibitor with high oral bioavailability and potential antitumor activity. The SMO inhibitor BMS-833923 inhibits the sound hedgehog factor (SHH) pathway protein SMO, thereby suppressing the SHH signaling pathway. SMO is a G protein-coupled receptor located downstream of the SHH ligand cell surface receptor Patched-1 in the SHH pathway; SMO is inhibited in the absence of the ligand Patched-1, while binding of the ligand to Patched-1 leads to increased SMO levels. The SHH signaling pathway plays a crucial role in cell growth, differentiation, and repair. Constitutive activation of this pathway is associated with uncontrolled cell proliferation and has been observed in various cancers.
BMS-833923 (XL-139) is a potent, selective, orally administered small molecule SMO receptor antagonist that inhibits the Hh signaling pathway[2][3] - Its mechanism of action involves binding to the transmembrane domain of SMO, preventing Hh ligands from activating SMO, and blocking downstream Gli transcription factor-mediated proliferation and survival of Hh-dependent cancer cells[2][3] - BMS-833923 (XL-139) has shown efficacy in vitro and in vivo against Hh pathway-dependent tumors, including basal cell carcinoma and prostate cancer[2][3] - Its efficacy in treating locally advanced or metastatic basal cell carcinoma and castration-resistant prostate cancer has been evaluated in preclinical studies[1][3] - BMS-833923 (XL-139) has been used as a tool compound to study Hh pathway signaling in solid tumors and to validate SMO. Effectiveness as a therapeutic target [2][3] |
| Molecular Formula |
C30H27N5O
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| Molecular Weight |
473.57
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| Exact Mass |
473.221
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| Elemental Analysis |
C, 76.09; H, 5.75; N, 14.79; O, 3.38
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| CAS # |
1059734-66-5
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| Related CAS # |
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| PubChem CID |
57662985
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| Appearance |
White solid powder
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| Density |
1.3±0.1 g/cm3
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| Index of Refraction |
1.704
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| LogP |
5.07
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
36
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| Complexity |
689
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| Defined Atom Stereocenter Count |
0
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| 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]
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| InChi Key |
KLRRGBHZCJLIEL-UHFFFAOYSA-N
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| 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)
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| Chemical Name |
N-[2-methyl-5-(methylaminomethyl)phenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| 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.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00909402 | Completed | Drug: BMS-833923 Drug: Cisplatin |
Stomach Neoplasms Esophageal Neoplasms |
Bristol-Myers Squibb | November 2009 | Phase 1 |
| NCT01218477 | Completed | Drug: Dasatinib Drug: BMS-833923 |
Leukemia | Bristol-Myers Squibb | January 2011 | Phase 1 Phase 2 |
| NCT00670189 | Completed | Drug: BMS-833923 (XL139) | Hedgehog Pathway Smoothened |
Bristol-Myers Squibb | July 2008 | Phase 1 |
| NCT01413906 | Completed | Drug: BMS-833923 (XL139) | Cancer | Bristol-Myers Squibb | November 2011 | Phase 1 |
| NCT02100371 | Completed | Drug: BMS-833923 | Basal Cell Nevus Syndrome | University Health Network, Toronto |
February 2014 | Not Applicable |
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