Synonym
GSK461364; GSK 461364; GSK-461364; GSK461364A; GSK 461364A; GSK-461364A
IUPAC/Chemical Name
(R)-5-(6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-1-yl)-3-(1-(2-(trifluoromethyl)phenyl)ethoxy)thiophene-2-carboxamide
InChi Key
ZHJGWYRLJUCMRT-QGZVFWFLSA-N
InChi Code
InChI=1S/C27H28F3N5O2S/c1-17(19-5-3-4-6-20(19)27(28,29)30)37-23-14-24(38-25(23)26(31)36)35-16-32-21-8-7-18(13-22(21)35)15-34-11-9-33(2)10-12-34/h3-8,13-14,16-17H,9-12,15H2,1-2H3,(H2,31,36)/t17-/m1/s1
SMILES Code
O=C(C1=C(O[C@@H](C2=CC=CC=C2C(F)(F)F)C)C=C(N3C=NC4=CC=C(CN5CCN(C)CC5)C=C34)S1)N
Appearance
white solid powder
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO, not in water
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
Phase I study of GSK-461364: Forty patients received GSK461364: 23 patients in schedule A and 17 in schedule B. Dose-limiting toxicities (DLT) in schedule A at 300 mg (2 of 7 patients) and 225 mg (1 of 8 patients) cohorts included grade 4 neutropenia and/or grade 3-4 thrombocytopenia. In schedule B, DLTs of grade 4 pulmonary emboli and grade 4 neutropenia occurred at 7 or more days at 100 mg dose level. Venous thrombotic emboli (VTE) and myelosuppression were the most common grade 3-4, drug-related events. Pharmacokinetic data indicated that AUC (area under the curve) and C(max) (maximum concentration) were proportional across doses, with a half-life of 9 to 13 hours. Pharmacodynamic studies in circulating tumor cells revealed an increase in phosphorylated histone H3 (pHH3) following drug administration. A best response of prolonged stable disease of more than 16 weeks occurred in 6 (15%) patients, including 4 esophageal cancer patients. Those with prolonged stable disease had greater expression of Ki-67, pHH3, and Plk1 in archived tumor biopsies. CONCLUSIONS: The final recommended phase II dose for GSK461364 was 225 mg administered intravenously in schedule A. Because of the high incidence (20%) of VTE, for further clinical evaluation, GSK461364 should involve coadministration of prophylactic anticoagulation. (source: Clin Cancer Res. 2011 May 15;17(10):3420-30.)
Biological target:
GSK461364 is a selective, reversible and ATP-competitive Polo-like kinase 1 (PLK1) inhibitor with a Ki value of 2.2 nM.
In vitro activity:
GSK461364 treatment also increased the proportion of sub-G1 cells, which includes apoptotic cells (Figure 2A). Treatment at GI80 resulted in slightly more sub-G1 cells than treatment at GI50, and the effect was most pronounced after 72 hours of treatment. This study confirmed that GI50 GSK461364 concentrations significantly induced apoptosis in SK-N-AS and IMR32 cells using the cell death detection ELISA™ (Figure 2C), and apoptotic cell fractions rose further when GSK461364 concentrations were increased to GI80 or 5-fold GI50. These data demonstrate that GSK461364 inhibits proliferation and induces both cell cycle arrest at the G2/M restriction point and apoptosis in neuroblastoma cells, regardless of MYCN status.
Reference: Oncotarget. 2017 Jan 24;8(4):6730-6741. https://pubmed.ncbi.nlm.nih.gov/28036269/
In vivo activity:
GSK461364 treatment also significantly reduced IMR32 xenograft tumor growth compared to the control group (Figure 4B, Supplementary Figure 2B). Immunohistological examination of xenograft tumors showed that GSK461364 reduced the number of proliferating cells and increased the number of apoptotic cells in tumors (Figure 4C). These data clearly demonstrate that GSK461364 treatment in vivo suppresses growth of xenografts derived from neuroblastoma cells with high-risk characteristics regardless of MYCN status.
Reference: Oncotarget. 2017 Jan 24;8(4):6730-6741. https://pubmed.ncbi.nlm.nih.gov/28036269/
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMF |
20.0 |
36.79 |
| DMSO |
56.7 |
104.24 |
| Ethanol |
60.0 |
110.37 |
| Ethanol:PBS (pH 7.2) (1:1) |
0.5 |
0.92 |
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
543.60
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
Formulation protocol:
1. Pajtler KW, Sadowski N, Ackermann S, Althoff K, Schönbeck K, Batzke K, Schäfers S, Odersky A, Heukamp L, Astrahantseff K, Künkele A, Deubzer HE, Schramm A, Sprüssel A, Thor T, Lindner S, Eggert A, Fischer M, Schulte JH. The GSK461364 PLK1 inhibitor exhibits strong antitumoral activity in preclinical neuroblastoma models. Oncotarget. 2017 Jan 24;8(4):6730-6741. doi: 10.18632/oncotarget.14268. PMID: 28036269; PMCID: PMC5351666.
In vitro protocol:
1. Pajtler KW, Sadowski N, Ackermann S, Althoff K, Schönbeck K, Batzke K, Schäfers S, Odersky A, Heukamp L, Astrahantseff K, Künkele A, Deubzer HE, Schramm A, Sprüssel A, Thor T, Lindner S, Eggert A, Fischer M, Schulte JH. The GSK461364 PLK1 inhibitor exhibits strong antitumoral activity in preclinical neuroblastoma models. Oncotarget. 2017 Jan 24;8(4):6730-6741. doi: 10.18632/oncotarget.14268. PMID: 28036269; PMCID: PMC5351666.
In vivo protocol:
1. Pajtler KW, Sadowski N, Ackermann S, Althoff K, Schönbeck K, Batzke K, Schäfers S, Odersky A, Heukamp L, Astrahantseff K, Künkele A, Deubzer HE, Schramm A, Sprüssel A, Thor T, Lindner S, Eggert A, Fischer M, Schulte JH. The GSK461364 PLK1 inhibitor exhibits strong antitumoral activity in preclinical neuroblastoma models. Oncotarget. 2017 Jan 24;8(4):6730-6741. doi: 10.18632/oncotarget.14268. PMID: 28036269; PMCID: PMC5351666.
1: Liu-Sullivan N, Zhang J, Bakleh A, Marchica J, Li J, Siolas D, Laquerre S, Degenhardt YY, Wooster R, Chang K, Hannon GF, Powers S. Pooled shRNA screen for sensitizers to inhibition of the mitotic regulator polo-like kinase (PLK1). Oncotarget. 2011 Dec;2(12):1254-64. PubMed PMID: 22248814.
2: 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. Epub 2011 Apr 1. PubMed PMID: 21459796.
3: Schöffski P. Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology. Oncologist. 2009 Jun;14(6):559-70. Epub 2009 May 27. Review. PubMed PMID: 19474163.
