Description
SB 218078 is an inhibitor of checkpoint kinase 1 (Chk1) that blocks phosphorylation of cdc25 with an IC50 value of 15 nM. It less potently inhibits cdc2 and PKC (IC50s = 250 and 1,000 nM, respectively) and causes 85% inhibition of PKD1 at 1 μM. SB 218078 releases G2 cell cycle arrest induced by γ-irradiation or the topoisomerase I inhibitor topotecan . In this way, SB 218078 enhances the cytotoxicity of DNA-damaging compounds.
Uses
SB 218078 is a selective inhibitor of Chk1.
Definition
ChEBI: LSM-1274 is an indolocarbazole.
Biological Activity
Inhibitor of checkpoint kinase 1 (Chk1) that displays selectivity over other protein kinases (IC 50 values are 15, 250 and 1000 nM for Chk1, cdc2 and PKC respectively). Abrogates G 2 cell cycle arrest caused by γ -irradiation and topoisomerase I inhibition. Potentiates cytotoxicity of DNA-damaging drugs, enhancing the efficacy of some chemotherapeutics.
in vitro
SB-218078 (2.5-5 μM; 18 hours; HeLa cells) treatment abrogates G2 cell cycle arrest caused by either γ-irradiation or a topoisomerase I Topotecan inhibition.SB-218078 (500-625 μM; 96 hours; HeLa and HT-29 cells) treatment significantly increases the cytotoxicity of DNA damage .
in vivo
SB-218078 (5 mg/kg; intraperitoneal injection; for 16 hours; C57/Bl6 mice) treatment could promote a strong increase of γ-H2AX and apoptosis throughout the lymphoma, while having no effect on a healthy spleen in Myc-induced lymphomas mouse model.
target
chk1, cdc2 and pkc
IC 50
15, 250 and 1000 nm for chk1, cdc2 and pkc respectively
References
[1] jackson j r, gilmartin a g, imburgia c s, et al. an indolocarbazole inhibitor of human checkpoint kinase (chk1) abrogates cell cycle arrest caused by dna damage[j]. cancer research, 2000, 60(3): 566-572.
[2] gasser s, orsulic s, brown e j, et al. the dna damage pathway regulates innate immune system ligands of the nkg2d receptor[j]. nature, 2005, 436(7054): 1186-1190.
[3] alderton g k, galbiati l, griffith e, et al. regulation of mitotic entry by microcephalin and its overlap with atr signalling[j]. nature cell biology, 2006, 8(7): 725-733.
[4] murga m, campaner s, lopez-contreras a j, et al. exploiting oncogene-induced replicative stress for the selective killing of myc-driven tumors[j]. nature structural & molecular biology, 2011, 18(12): 1331-1335.
