WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 205667
Description: GSK-461364 is a Polo-like kinase 1 inhibitor, is also a small molecule Polo-like kinase 1 (PLK1) inhibitor with potential antineoplastic activity. Polo-like kinase 1 inhibitor GSK461364 selectively inhibits Plk1, inducing selective G2/M arrest followed by apoptosis in a variety of tumor cells while causing reversible cell arrest at the G1 and G2 stage without apoptosis in normal cells. Plk1, named after the polo gene of Drosophila melanogaster, is a serine/threonine protein kinase involved in regulating mitotic spindle function in a non-ATP competitive manner.
MedKoo Cat#: 205667
Chemical Formula: C27H28F3N5O2S
Exact Mass: 543.19158
Molecular Weight: 543.60373
Elemental Analysis: C, 59.66; H, 5.19; F, 10.48; N, 12.88; O, 5.89; S, 5.90
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
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.)
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: SchÃ¶ffski 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.