using HIM TNBC xenograft designs offer proof of principle that TNBCs harboring TP53 variations may be effectively targeted by the combination of a DNA damaging agent followed by a Chk1 inhibitor. This synthetic lethal method Ubiquitin ligase inhibitor is founded on a tumor specific mutation and a drug, in this situation a DNA damaging agent along with a Chk1 inhibitor, acting together to trigger the tumor cell to undergo apoptosis, like the synthetic lethal connections of BRCA1 mutations and poly polymerase inhibitors. WU BC5 was derived from a mind metastasis, which harbors 50 checked position versions, little indels, and important copy number variations, from the same patient who was afflicted by complete genome sequencing analysis mentioned above. Regardless of the complexity of the back ground, WU BC5 was vulnerable to the mixture of a DNA harmful agent and a Chk1 chemical, which is likely because of TP53 mutation. Our research provides preclinical basis for the clinical study of this strategy in TNBC. Our phase I trial evaluating the mix of irinotecan Metastasis and UCN 01 in patients with higher level solid tumor malignancies showed promise in patients with TNBC, and the expansion phase of the trial is currently being done in patients with metastatic TNBC. It is interesting to note that the 2 HIM designs that responded to the combination therapy were both basal like by molecular subtyping, whereas WU BC3 is HER2 E and did not respond. While a sub-type specific antitumor response to the combination therapy may be a possibility, the superior apoptotic response of WU BC3 to the combination therapy when p53 was pulled down in these cells argues from this possibility. Along with while AZD7706 can be a more selective Chk1 inhibitor, Chk1, UCN 01 targets other kinases, including Canagliflozin chemical structure PDK1 in the PI3K pathway. Provided that UCN 01, but not AZD7762, inhibits PDK1, yet both agents induced checkpoint bypass and apoptosis in TP53 mutant TNBC, we conclude that Chk1 inhibition, not PDK1 inhibition, will be the mechanism of anti-tumor effect of these inhibitors. Moreover, AZD7762, however not UCN 01, can be a potent Chk2 inhibitor, arguing that Chk1, in place of Chk2, inhibition accounts for the antitumor effects observed with your protein kinase inhibitors. In support of this conclusion, a selective Chk2 inhibitor was not able to induce checkpoint bypass or enhance the DNA damage and apoptotic consequences of irinotecan in the p53 knock-down cell line BC3 p53KD. This is consistent with previous findings reporting that knockdown of Chk1 in the existence of endogenous Chk2 is sufficient to abrogate S and G2 check-points in cells with DNA damage, while Chk2 knockdown doesn’t induce checkpoint bypass nor does Chk2 knockdown synergize with Chk1 knockdown to potentiate checkpoint bypass.