|Chk1 and MK2 Inhibitors set Chk1- and MK2 inhibitors|
Sample solution is provided at 25 µL, 10mM.
Publications citing ApexBio Products
PF477736 and PF3644022 are potent and selective Chk1- and MK2 inhibitors, respectively.The simultaneous Chk1- and MK2 inhibition with PF477736 and PF3644022 is proposed as a therapeutic strategy for the treatment of KRAS-or BRAF-driven cancers. 
Chk1 and MK2 are both critical components of the G2/M checkpoint, which are essential for avoiding mitotic entry of cells suffering from genotoxic damage .Chk1 and Chk2 are important effector kinases in the canonical DNA damage response (DDR) network through the upstreamkinases ATR and ATM (Jackson and Bartek, 2009).The p38/MK2 pathway is a widespread stress-kinase pathway that operates in parallel to Chk1. Chk1 and MK2 control checkpoint initiation and maintenance, respectively . The activity of both kinases converges on mediating inhibitory phosphorylations onCDC25 familymembers to induce a subsequent cell-cycle arrest by blocking CDC25B-dependent CDK activation .
KRAS is one of the most frequently mutated onco-genes in human cancer. Acute expression of oncogenic KRAS induces genotoxic damage. Oncogenic KRAS mutations are associated with addiction to Chk1-/MK2-mediated checkpoints. 
Strong synergistic effects in cell-cycle checkpoint had been shown between PF477736 and PF3644022 in 33 out of the 96 cell lines, speciﬁcally in KRAS- and BRAF-driven cells. KRAS-mutant cancer displays intrinsic genotoxic stress, leading to tonic Chk1- and MK2 activity. Co-treatment of PF477736 and PF3644022leads to mitotic catastrophe in KRAS-mutant cells. 
In xenograft mice models, including distinct Kras-or Braf-driven autochthonous murine cancer models, this actionable synergistic interaction is validated. In KRAS-or BRAF-mutant tumorcells directly isolated from patients, the combined checkpoint inhibition induces apoptotic cell death. 
1.Dietlein F, Kalb B2, Jokic M et al.A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer.Cell. 2015 Jul 2;162(1):146-59.
2.Reinhardt, H.C., and Yaffe, M.B. (2013). Phospho-Ser/Thr-binding domains: navigating the cell cycle and DNA damage response. Nat. Rev. Mol. Cell Biol. 14, 563–580.
3.Jackson, S.P., and Bartek, J. The DNA-damage response in humanbiology and disease. Nature. 2009. 461, 1071–1078.
4.Reinhardt, H.C., Hasskamp, P., Schmedding, I., et al. DNA damage activates a spatially distinct late cytoplasmic cell-cycle checkpoint network controlled by MK2-mediated RNA stabilization. 2010. Mol. Cell 40, 34–49.