Things Aurora B inhibitor BI-1356 Specialists Should Teach You

the BCR Abl fusion protein is constitutively active, driving autophosphorylation of residue tyrosine 245 and phosphorylation of a downstream target CrkL oThough the ATM connected kinase, ATR, was not inhibited by CP466722 in vitro, inhibitory actions against abl and src kinases were noted in this in vitro screen.

Disruption of ATM dependent phosphorylation events also as inhibition of ATM dependent p53 induction were also observed in MCF 7 human breast cancer cells and principal and immortalized diploid human fibroblasts. General, the response to IR in cells treated with CP466722 was similar to that witnessed in cells lacking ATM. Because a single long term goal would be to characterize the potential Aurora B inhibitor of CP466722 to sensitize tumors to radiation or chemotherapeutic agents in murine models in vivo, it was important to know if CP466722 was effective at inhibiting Atm kinase in mouse cells. The ATM signaling pathway is conserved from human to mouse and ATM kinase activity can be monitored by analyzing similar downstream events. An exception is phosphorylation of Chk2 on threonine 68 which is difficult to detect in mouse cells.

While ATM is preferentially activated by DSBs and phosphorylates Chk2 on threonine 68, ATR is preferentially activated by stalled replication forks and phosphorylates serine 345 of Chk1. Though CP466722 BI-1356 did not affect ATR kinase activity in vitro, we examined the ability of the compound to affect ATR kinase activity in cells. hTERT immortalized human fibroblasts were treated for 1h with the replication inhibitor aphidicolin in the presence or absence of CP466722. ATR dependent phosphorylation of Chk1 was not inhibited by CP466722, even though ATM dependent phosphorylation of Chk2 was blocked in these cells. Failure to inhibit aphidicolin induced Chk1 phosphorylation in cells lacking ATM provided even more definitive evidence that CP466722 does not inhibit ATR kinase in cells.

Serum starvation resulted in an almost complete loss of AKT phosphorylation.