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GSK923295 (also called GSK-923295; GSK923295A; GSK 923295; GSK-923295A) is a first-in-class, specific and allosteric antimitotic inhibitor of CENP-E (centromere-associated protein E, kinesin motor ATPase) with potential antitumor activity. It inhibits CENP-E with a Ki of 3.2 nM, and it is less potent against mutant I182 and T183. GSK923295A has demonstrated high antitumor activity against various solid tumor models such as CRs in rhabdoid, Ewing sarcoma, and rhabdomyosarcoma xenografts.
Physicochemical Properties
| Molecular Formula | C32H38CLN5O4 | |
| Molecular Weight | 592.13 | |
| Exact Mass | 591.261 | |
| CAS # | 1088965-37-0 | |
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| PubChem CID | 46898058 | |
| Appearance | White to yellow solid powder | |
| Density | 1.25 | |
| Melting Point | 197-198℃ | |
| LogP | 5.295 | |
| Hydrogen Bond Donor Count | 3 | |
| Hydrogen Bond Acceptor Count | 6 | |
| Rotatable Bond Count | 12 | |
| Heavy Atom Count | 42 | |
| Complexity | 870 | |
| Defined Atom Stereocenter Count | 2 | |
| SMILES | C[C@@H](C1=CC=CN2C1=NC(=C2)C3=CC=C(C=C3)C[C@@H](CNC(=O)CN(C)C)NC(=O)C4=CC(=C(C=C4)OC(C)C)Cl)O |
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| InChi Key | WHMXDBPHBVLYRC-OFVILXPXSA-N | |
| InChi Code | InChI=1S/C32H38ClN5O4/c1-20(2)42-29-13-12-24(16-27(29)33)32(41)35-25(17-34-30(40)19-37(4)5)15-22-8-10-23(11-9-22)28-18-38-14-6-7-26(21(3)39)31(38)36-28/h6-14,16,18,20-21,25,39H,15,17,19H2,1-5H3,(H,34,40)(H,35,41)/t21-,25-/m0/s1 | |
| Chemical Name | 3-chloro-N-[(2S)-1-[[2-(dimethylamino)acetyl]amino]-3-[4-[8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl]phenyl]propan-2-yl]-4-propan-2-yloxybenzamide | |
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| 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 |
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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) |
Biological Activity
| ln Vitro | GSK-923295 (GSK923295) is an allosteric inhibitor of CENP-E kinesin motor activity that is unique in its class. With a Ki of 3.2± 0.2 nM for humans and 1.6±0.1 nM for dogs, GSK923295 inhibits CENP-E MT-stimulated ATPase activity without being competitive with either ATP or MT. Inorganic phosphate release is inhibited by GSK923295, and CENP-E motor domain association with microtubules is stabilized[1]. IC50s for GSK923295's broad growth inhibitory activity in a panel of 237 cancer cell lines are 17.2 nM, 55.6 nM, 42 nM, and 51.9 nM for SW48, RKO (BRAF mutant), SW620 (KRAS mutant), and HCT116 (KRAS mutant), respectively. Eight of the eleven mouse xenograft tumor models exhibit significant tumor growth-delay[2]. With a Ki of 3.2 nM, GSK923295 is a strong and specific small molecule inhibitor of human CENPE. With an average growth IC50 of 41 nM, GSK923295 exhibits broad effectiveness against a panel of 19 human neuroblastoma derived cell lines[3]. | ||
| ln Vivo | In comparison to the control arm, the xenografts of mice treated with GSK-923295 (GSK923295) exhibit a significant delay in tumor growth (NB-EBc1 p<0.0001; NB-1643 p=0.018; NB-1691 p=0.0018)[3]. | ||
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| References |
[1]. Antitumor activity of an allosteric inhibitor of centromere-associated protein-E. Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5839-44. [2]. Mitogen-activated protein kinase (MEK/ERK) inhibition sensitizes cancer cells to centromere-associated protein E (CENP-E) inhibition. Int J Cancer. 2013 Feb 1;132(3):E149-57. [3]. Serial transcriptome analysis and cross-species integration identifies centromere-associated protein E as a novel neuroblastoma target. Cancer Res. 2010 Apr 1;70(7):2749-58. |
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| Additional Infomation |
GSK-923295 is a small-molecule inhibitor of the mitotic kinesin centromere-associated protein E (CENP-E), and the third novel drug candidate to arise from Cytokinetics' broad strategic alliance with GlaxoSmithKline (GSK). GSK-923295 demonstrated a broad spectrum of activity against a range of human tumor xenografts grown in nude mice, including models of colon, breast, ovarian, lung and other tumors. GSK-923295 is the first drug candidate to enter human clinical trials that specifically targets CENP-E and is currently in Phase I human clinical trials being conducted by GSK. CENP-E Inhibitor GSK-923295A is a small-molecule inhibitor of the mitotic kinesin centromere-associated protein E (CENP-E), with potential antineoplastic activity. Upon administration, GSK-923295A binds to and inhibits CENP-E, thereby preventing cell division, inducing cell cycle arrest, and ultimately leading to an inhibition of cell proliferation. CENP-E, a kinetochore-associated mitotic kinesin, plays an essential role in chromosome movement during mitosis and regulates cell-cycle transition from metaphase to anaphase. Drug Indication Investigated for use/treatment in cancer/tumors (unspecified) and solid tumors. Mechanism of Action GSK-923295 is an inhibitor of the mitotic kinesin centromere-associated protein E (CENP-E). CENP-E plays an essential role in chromosome movement during early cell division or mitosis and integrates mitotic spindle mechanics with regulators of the mitotic checkpoint regulating cell-cycle transition from metaphase to anaphase. Inhibition of CENP-E induces cell cycle arrest during cell duplication leading to subsequent apoptosis or cell death. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3 mg/mL (5.07 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 30.0 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: 3 mg/mL (5.07 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 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: ≥ 3 mg/mL (5.07 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 30.0 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 | 1.6888 mL | 8.4441 mL | 16.8882 mL | |
| 5 mM | 0.3378 mL | 1.6888 mL | 3.3776 mL | |
| 10 mM | 0.1689 mL | 0.8444 mL | 1.6888 mL |