GSK461364

• CAT Number: I005526
• CAS Number: 929095-18-1
• Molecular Formula: C₂₇H₂₈F₃N₅O₂S
• Molecular Weight: 543.6
• Purity: ≥95%
• Synonyms: GSK-461364
• Target: PLK
• Solubility: DMSO ≥9mg/mL Water <1.2mg/mL Ethanol ≥60mg/mL
• Storage: 3 years -20C powder
• IC50: 2.2 nM(Ki)
• InChI: 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
• InChIKey: ZHJGWYRLJUCMRT-QGZVFWFLSA-N
• 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

GSK461364 is a potent small molecule Polo-like kinase 1 (PLK1) inhibitor with a Ki of 2.2 nM. 


in vitro: GSK461364 is a potent inhibitor of cell proliferation causing 50% growth inhibition (GI50) below 100 nM in most of the cell lines tested with limited toxicity against human nonproliferating cells. Inhibition of cell cycle progression is concentration dependent with initial delay at G2 phase at high GSK461364 concentrations and arrest at M phase at lower concentrations. Currently, GSK461364 is in a dose-escalation first-time-in-human trial. Cell lines with mutations in the TP53 gene tended to be more sensitive to GSK461364, and that inhibiting the p53 response by RNA silencing confers increased sensitivity in some p53 wild-type (WT) cells. Furthermore, these more sensitive cell lines also have increased levels of chromosome instability, a characteristic associated with TP53 mutations. In preclinical testing, GSK461364 shows antiproliferative activity against multiple (>120) tumor cell lines and potently inhibits the proliferation of greater than 83% and 91% of these cell lines, with IC50 values lower than 50 and 100 nM, respectively. 


in vivo: GSK461364 shows a dose-dependent mitotic arrest in mouse xenografts, which correlates with effects on tumor growth. Intraperitoneal administration of GSK461364 causes regression or tumor growth delay in different xenograft models, including Colo205 xenografts. Suppression of Plk1 in vivo by using GSK461364 results in mitotic arrest with aberrant mitotic figures consisting of monopolar or collapsed mitotic spindles.

Reference

1:The GSK461364 PLK1 inhibitor exhibits strong antitumoral activity in preclinical neuroblastoma models. 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.Oncotarget. 2017 Jan 24;8(4):6730-6741. doi: 10.18632/oncotarget.14268. PMID: 28036269 Free PMC Article2:Cytotoxic mechanism of PLK1 inhibitor GSK461364 against osteosarcoma: Mitotic arrest, apoptosis, cellular senescence, and synergistic effect with paclitaxel. Chou YS, Yen CC, Chen WM, Lin YC, Wen YS, Ke WT, Wang JY, Liu CY, Yang MH, Chen TH, Liu CL.Int J Oncol. 2016 Mar;48(3):1187-94. doi: 10.3892/ijo.2016.3352. Epub 2016 Jan 20. PMID: 26794530 3:Overexpression of human ABCB1 in cancer cells leads to reduced activity of GSK461364, a specific inhibitor of polo-like kinase 1. Wu CP, Hsiao SH, Luo SY, Tuo WC, Su CY, Li YQ, Huang YH, Hsieh CH.Mol Pharm. 2014 Oct 6;11(10):3727-36. doi: 10.1021/mp500492r. Epub 2014 Sep 18. PMID: 25192198 4:BI 6727 and GSK461364 suppress growth and radiosensitize osteosarcoma cells, but show limited cytotoxic effects when combined with conventional treatments. Bogado RF, Pezuk JA, de Oliveira HF, Tone LG, Brassesco MS.Anticancer Drugs. 2015 Jan;26(1):56-63. doi: 10.1097/CAD.0000000000000157. PMID: 25089571 5:Phase I study of GSK461364, a specific and competitive Polo-like kinase 1 inhibitor, in patients with advanced solid malignancies. 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.Clin Cancer Res. 2011 May 15;17(10):3420-30. doi: 10.1158/1078-0432.CCR-10-2946. Epub 2011 Apr 1. PMID: 21459796 Free Article