GSK461364
GSK461364 is a potent and reversible ATP competitive Plk1 inhibitor. Polo-like kinases (Plk) are a family of serine threonine kinases that are critical regulators of DNA damage response and cell cycle progression.
In vitro: GSK461364 showed at least 390-fold greater selectivity for Plk1 than for Plk2 and Plk3 and 1,000-fold greater than for 48 other kinases. The drug showed antiproliferative activity against multiple (>120) tumor cell lines and potently inhibited the proliferation of greater than 83% and 91% of these cell lines [1].
In vivo: Intraperitoneal administration of GSK461364 caused regression or tumor growth delay in different xenograft models. In vivo suppression of Plk1 by using GSK461364 resulted in mitotic arrest with aberrant mitotic figures consisting of monopolar or collapsed mitotic spindles [1].
Clinical trial: The final recommended phase II dose for GSK461364 was 225 mg administered intravenously. Moreover, GSK461364 was suggested to involve coadministration of prophylactic anticoagulation for further clinical evaluation [1].
Reference:
[1] Olmos D, Barker D, Sharma R, Brunetto AT, Yap TA, Taegtmeyer AB, Barriuso J, Medani H, Degenhardt YY, Allred AJ, Smith DA, Murray SC, Lampkin TA, Dar MM, Wilson R, de Bono JS, Blagden SP.? Phase I study of GSK461364, a specific and competitive Polo-like kinase 1 inhibitor, in patients with advanced solid malignancies. Clin Cancer Res. 2011 May 15;17(10):3420-30.
- 1. Velpurisiva P, Rai P. "Synergistic Action of Gefitinib and GSK41364A Simultaneously Loaded in Ratiometrically-Engineered Polymeric Nanoparticles for Glioblastoma Multiforme." J Clin Med. 2019 Mar 15;8(3). pii: E367. PMID:30875975
- 2. Velpurisiva P, Piel BP, et al. "GSK461364A, a Polo-Like Kinase-1 Inhibitor Encapsulated in Polymeric Nanoparticles for the Treatment of Glioblastoma Multiforme (GBM)." Bioengineering (Basel). 2018 Oct 9;5(4). pii: E83. PMID:30304810
- 3. Higuchi F, Fink AL, et al."PLK1 inhibition targets Myc-activated malignant glioma cells irrespective of mismatch repair deficiency-mediated acquired resistance to temozolomide." Mol Cancer Ther. 2018 Sep 14. pii: molcanther.0177.2018. PMID:30217967
| Storage | Store at -20°C |
| M.Wt | 543.6 |
| Cas No. | 929095-18-1 |
| Formula | C27H28F3N5O2S |
| Solubility | insoluble in H2O; ≥15.65 mg/mL in EtOH; ≥49.5 mg/mL in DMSO |
| Chemical Name | 5-[6-[(4-methylpiperazin-1-yl)methyl]benzimidazol-1-yl]-3-[(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy]thiophene-2-carboxamide |
| SDF | Download SDF |
| Canonical SMILES | CC(C1=CC=CC=C1C(F)(F)F)OC2=C(SC(=C2)N3C=NC4=C3C=C(C=C4)CN5CCN(CC5)C)C(=O)N |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Cell experiment [1]: | |
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Cell lines |
Human adult glioblastoma T98G cell lines and pediatric SF188 cell lines |
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Preparation method |
The solubility of this compound in DMSO is > 15.65 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
75, 150 and 300 nM, 72 h, |
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Applications |
After 72 h treatment, GSK461364 caused a significant decrease of proliferation in GBM T98G cells and SF188 cells. |
| Clinical experiment [2]: | |
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Animal models |
18 years or older patients with a confirmed diagnosis of advanced solid tumor for which no effective treatment was available. |
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Dosage form |
Intravenous infusion, 50 mg, once a week or 25 mg, twice a week, dose was escalated with treatment |
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Application |
After the end of the 4-hour infusion, GSK461364 plasma concentrations declined bi-exponentially. Distribution of GSK461364 was initially rapid and plasma concentrations decreased to approximately 15% to 20% of the Cmax within 8 hours of cessation of infusion. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1]. Pezuk J A, Brassesco M S, Morales A G, et al. Polo-like kinase 1 inhibition causes decreased proliferation by cell cycle arrest, leading to cell death in glioblastoma[J]. Cancer gene therapy, 2013, 20(9): 499-506. [2]. Olmos D, Barker D, Sharma R, et al. Phase I study of GSK461364, a specific and competitive Polo-like kinase 1 inhibitor, in patients with advanced solid malignancies[J]. Clinical Cancer Research, 2011, 17(10): 3420-3430. | |
| Description | GSK461364 is a inhibitor of Plk1 with a Ki value of 2.2 nM. | |||||
| Targets | PLK1 | |||||
| IC50 | 2.2 nM(Ki) | |||||
Quality Control & MSDS
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Chemical structure
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