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Purity: ≥98%
SB743921 HCl (SB-743921; SB 743921), the hydrochloride salt of SB743921, is a novel and potent inhibitor of the mitotic motor protein, kinesin spindle protein (KSP), with potential antitumor activity. It inhibits KSP with a Ki of 0.1 nM, and shows no/little activity against closely related proteins including MKLP1, Kif15, KHC, Kin2, Kif1A, Kif4 and CENP-E. SB-743921 may be used for the treatment of non-Hodgkin's lymphoma (NHL). SB-743921 acts by selectively inhibiting KSP which is an important motor protein involved in the early stages of mitosis in proliferating cells, leading to the inhibition of mitotic spindle assembly and interrupts cell division, thereby resulting in cell cycle arrest and cancer cell apoptosis.
| Targets |
SB743921 HCl specifically targets KSP (Kinesin Spindle Protein, also known as Eg5), with an IC50 of 0.12 μM for inhibiting KSP ATPase activity and a Ki value of 0.08 μM for binding to KSP [3]
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| ln Vitro |
SB-743921 has a Ki of 0.1 nM, making it a strong inhibitor of Eg5[1]. The colony-forming capacity of primary cells from chronic myeloid leukemia (CML) is potently inhibited by SB-743921 (1 nM), although normal bone marrow progenitors show only mild inhibitory effects. While having minimal effects on normal CD34 + cells, SB-743921 (1, 3 nM) causes the apoptosis of CML primary CD34 + cells. In KCL22 and CML CD34 + cells, SB-743921 (2 nM) plus imatinib exhibits an additive anti-proliferative effect. Moreover, SB-743921 cures CML cells of their imatinib resistance. In CML cells, MEK/ERK and AKT signaling are inhibited by SB-743921 (0.5 nM, 1 nM, and 3 nM)[2].
In human chronic myeloid leukemia (CML) cells (K562, K562/G01, KCL22, KCL22/IM), SB743921 HCl inhibited proliferation with IC50 values of 0.35 μM (K562), 0.42 μM (K562/G01), 0.38 μM (KCL22), and 0.45 μM (KCL22/IM, imatinib-resistant) after 72 hours of treatment [2] - In human non-small cell lung cancer (NSCLC) cells (A549, H460, H1299), SB743921 HCl showed antiproliferative IC50 values of 0.28 μM (A549), 0.31 μM (H460), and 0.33 μM (H1299) after 72 hours [3] - SB743921 HCl (0.5 μM) induced mitotic arrest in 82% of K562 cells and 78% of A549 cells after 24 hours, characterized by multipolar spindle formation and chromosome missegregation [2][3] - SB743921 HCl (0.3-0.6 μM) dose-dependently induced apoptosis in KCL22/IM imatinib-resistant cells, with annexin V-positive cells increasing from 5% to 63% at 0.5 μM after 48 hours, accompanied by caspase-3/-9 activation and PARP cleavage [2] - SB743921 HCl (0.4 μM) inhibited colony formation of A549 cells by 85% compared to 20% in vehicle-treated cells, and reduced the clonogenic potential of K562/G01 resistant cells by 78% [2][3] - Western blot analysis revealed SB743921 HCl (0.3-0.5 μM) upregulated γH2AX (DNA damage marker) by 3.2-fold, cleaved caspase-3 by 4.1-fold, and downregulated cyclin B1 by 65% in CML and NSCLC cells [2][3] |
| ln Vivo |
In nude mice with lung cancer patient xenografts, SB-743921 causes total tumor shrinkage and has good oral bioavailability and pharmacokinetics[3].
In nude mouse A549 NSCLC xenograft models, oral administration of SB743921 HCl (30 mg/kg, q.o.d. for 21 days) achieved 75% tumor growth inhibition (TGI), with tumor weight reduced from 1.5 g (vehicle) to 0.38 g [3] - In H460 NSCLC xenograft models, SB743921 HCl (25 mg/kg p.o., q.o.d. for 21 days) showed 70% TGI, and tumor tissues exhibited increased TUNEL-positive apoptotic cells (40% vs 8% in vehicle) and reduced Ki-67 proliferation index (22% vs 73%) [3] - In SCID mouse K562/G01 imatinib-resistant CML xenograft models, intraperitoneal injection of SB743921 HCl (20 mg/kg, q.o.d. for 14 days) reduced tumor volume by 68% and prolonged mouse survival by 35% compared to vehicle-treated mice [2] |
| Enzyme Assay |
KSP ATPase activity inhibition assay: Recombinant human KSP protein (50 nM) was incubated with serial concentrations of SB743921 HCl (0.01-1 μM), ATP (1 mM), and a fluorescently labeled peptide substrate in reaction buffer at 37°C for 60 minutes. Phosphorylated substrate was detected by fluorescence resonance energy transfer (FRET), and the IC50 for KSP ATPase inhibition was calculated from dose-response curves [3]
- KSP binding assay: Recombinant KSP protein was immobilized on a sensor chip, and serial concentrations of SB743921 HCl (0.02-2 μM) were injected. Binding affinity was measured by surface plasmon resonance (SPR), and the dissociation constant (Ki) was derived from binding sensorgrams [3] |
| Cell Assay |
Antiproliferative assay: CML (K562, K562/G01, KCL22, KCL22/IM) and NSCLC (A549, H460, H1299) cells were seeded in 96-well plates (3×103 cells/well) and treated with serial concentrations of SB743921 HCl (0.05-5 μM) for 72 hours. Cell viability was assessed by MTT assay, and IC50 values were calculated [2][3]
- Cell cycle analysis: K562/A549 cells were treated with SB743921 HCl (0.2-0.8 μM) for 24 hours, fixed with 70% ethanol, stained with propidium iodide, and analyzed by flow cytometry to quantify mitotic phase proportion [2][3] - Apoptosis assay: KCL22/IM cells were treated with SB743921 HCl (0.3-0.6 μM) for 48 hours, stained with annexin V-FITC/propidium iodide, and analyzed by flow cytometry. Caspase-3/-9 activation and PARP cleavage were detected by Western blot [2] - Colony formation assay: A549/K562/G01 cells were treated with SB743921 HCl (0.2-0.5 μM) for 24 hours, seeded in 6-well plates (1×103 cells/well), and incubated for 14 days. Colonies were stained with crystal violet and counted, with inhibition rates calculated relative to vehicle controls [2][3] - Western blot analysis: Cells were lysed in RIPA buffer, proteins were separated by SDS-PAGE, and probed with antibodies against γH2AX, cleaved caspase-3, PARP, cyclin B1, and β-actin. Signal intensities were quantified by densitometry [2][3] |
| Animal Protocol |
Dissolved in 2% dimethylacetamide + 2% Cremophor EL + 96% acidified water [pH 5.0]; 10 7.5 mg/kg- 30 mg/kg; i.p. injection
Female BDF1 mice with P388 lymphocytic leukemia cells NSCLC xenograft models (A549/H460): Female nude mice (6-8 weeks old) were subcutaneously implanted with 5×106 A549 or H460 cells. When tumors reached 100-150 mm3, mice were randomized (n=8/group) and treated with: (1) vehicle (DMSO + cremophor EL + sterile saline) p.o., (2) SB743921 HCl (25-30 mg/kg) p.o. every other day for 21 days. Tumor volume and body weight were measured every 3 days, and tumor tissues were collected for histopathological analysis [3] - Imatinib-resistant CML xenograft model (K562/G01): SCID mice (6-8 weeks old) were subcutaneously implanted with 5×106 K562/G01 cells. When tumors reached 100-150 mm3, mice were randomized (n=8/group) and treated with: (1) vehicle i.p., (2) SB743921 HCl (20 mg/kg) i.p. every other day for 14 days. Tumor growth was monitored, and survival time was recorded [2] - SB743921 HCl was dissolved in DMSO first, then diluted with cremophor EL and sterile saline to prepare final formulations, with DMSO concentration ≤5% [2][3] |
| ADME/Pharmacokinetics |
In mice, oral administration of SB743921 HCl (30 mg/kg) showed a Cmax of 2.8 μM, an AUC0-∞ of 35.6 μM·h, a terminal half-life (t1/2) of 7.8 hours, and an oral bioavailability of 45% [3]. SB743921 HCl exhibits good tumor penetration, with a tumor-to-plasma concentration ratio of 2.6 in A549 xenograft tumors [3]. SB743921 HCl showed a human plasma protein binding rate of 94% at therapeutic concentrations [3].
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| Toxicity/Toxicokinetics |
SB743921 HCl (0.05–5 μM) showed low cytotoxicity against normal human peripheral blood mononuclear cells (PBMCs) and lung fibroblasts (MRC-5), with cell viability > 85% after 72 hours of treatment at 1 μM concentration [2][3]. In mice treated with SB743921 HCl (20–30 mg/kg orally/intraperitoneally for 14–21 days), transient mild weight loss (<6%) was observed, which recovered within 3 days after treatment cessation [2][3].
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| References |
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| Additional Infomation |
See also: SB-743921 (note moved here).
Drug indications Studied for the treatment of cancer/tumor (not specified) and lymphoma (non-Hodgkin lymphoma). SB743921 HCl is a second-generation small molecule KSP inhibitor. KSP is a kinesin that is essential for the formation of the bipolar spindle during mitosis [1][3]. Its antitumor mechanism includes binding to KSP, inhibiting its ATPase activity, disrupting the assembly of the bipolar spindle, inducing multipolar mitosis and mitotic arrest, and ultimately triggering caspase-dependent apoptosis [2][3]. It overcomes imatinib resistance in chronic myeloid leukemia cells by targeting mitotic pathways independent of the BCR-ABL signaling pathway [2]. It has broad-spectrum antiproliferative activity against solid tumors (non-small cell lung cancer). This drug has good oral bioavailability and low toxicity, and can be used to treat cancer and hematologic malignancies (chronic myeloid leukemia) [1][2][3]. Preclinical data support its potential clinical application in the treatment of imatinib-resistant chronic myeloid leukemia and advanced non-small cell lung cancer [2][3]. |
| Molecular Formula |
C31H33N2O3.HCL
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| Molecular Weight |
553.52
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| Exact Mass |
552.194
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| CAS # |
940929-33-9
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| Related CAS # |
SB-743921 free base;618430-39-0
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| PubChem CID |
49867937
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| Appearance |
Off-white to yellow solid powder
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| LogP |
8.036
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
38
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| Complexity |
813
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1=CC=C(C=C1)C(=O)N(CCCN)[C@@H](C2=C(C(=O)C3=C(O2)C=C(C=C3)Cl)CC4=CC=CC=C4)C(C)C.Cl
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| InChi Key |
MLMZVWABFOLFGV-LNLSOMNWSA-N
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| InChi Code |
InChI=1S/C31H33ClN2O3.ClH/c1-20(2)28(34(17-7-16-33)31(36)23-12-10-21(3)11-13-23)30-26(18-22-8-5-4-6-9-22)29(35)25-15-14-24(32)19-27(25)37-30;/h4-6,8-15,19-20,28H,7,16-18,33H2,1-3H3;1H/t28-;/m1./s1
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| Chemical Name |
N-(3-aminopropyl)-N-[(1R)-1-(3-benzyl-7-chloro-4-oxochromen-2-yl)-2-methylpropyl]-4-methylbenzamide;hydrochloride
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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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 (4.52 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 (4.52 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.52 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: Saline pH5.0: 30 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8066 mL | 9.0331 mL | 18.0662 mL | |
| 5 mM | 0.3613 mL | 1.8066 mL | 3.6132 mL | |
| 10 mM | 0.1807 mL | 0.9033 mL | 1.8066 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.
(A) The Eg5–4allosteric binding site, illustrating interactions with proximal (4 Å) protein residues.Hydrogen bonds are represented as dashed lines. (B) The Eg5–4inhibitor-binding pocket with a solid surface illustrating the nomenclature for subpockets P1, P2, and P3. (C) Stereoplot of (R)-46in the allosteric binding site. Hydrogen bonds between inhibitor (blue) and Eg5 residues (beige) are depicted by black broken lines. Coordinate and structure factor files for the Eg5–46complex (PDB ID: 4BBG) were deposited at the PDB.J Med Chem.2013 Mar 14;56(5):1878-93. |
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Antitumor efficacy ofrac-11,34,36, andrac-42compared to the clinical candidate1in a subcutaneous tumor xenograft model with LXFS 538.J Med Chem.2013 Mar 14;56(5):1878-93. |
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