MK-1775 CAS:955365-80-7

¿Qué es MK-1775??

MK-1775 es un inhibidor del punto de control quinasa Wee1 (IC50 = 5.2 Nuevo Méjico).1 Se ha demostrado que inhibe la fosforilación de Cdc2 en la triposina-15., que anula el punto de control de daño del ADN G2.1 En tumores con deficiencia de p53 que dependen únicamente del punto de control G2 sobre el daño del ADN, MK-1775, en combinación con agentes quimioterapéuticos que dañan el ADN, is reported to induce apoptosis in vitro and potentiate the inhibition of tumor growth in vivo.

MK-1775 treatment led to the inhibition of Wee1 kinase and reduced inhibitory phosphorylation of its substrate Cdc2. MK-1775, when dosed with gemcitabine, abrogated the checkpoint arrest to promote mitotic entry and facilitated tumor cell death as compared to control and gemcitabine treated tumors. MK-1775 monotherapy did not induce tumor regressions. Sin embargo, the combination of gemcitabine with MK-1775 produced robust anti-tumor activity and remarkably enhanced tumor regression response (4.01 fold) compared to gemcitabine treatment in p53-deficient tumors. Tumor re-growth curves plotted after the drug treatment period suggest that the effect of the combination therapy is longer-lasting than that of gemcitabine. None of the agents produced tumor regressions in p53-wild type xenografts.

MK-1775 inhibits Wee1 kinase in an ATP-competitive manner. Compared to Wee1, MK-1775 displays 2- to 3-fold less potency against Yes with IC50 of 14 Nuevo Méjico, 10-fold less potency against seven other kinases with >80% inhibition at 1 µM, y >100-fold selectivity over human Myt 1, another kinase that inhibits cyclin-dependent kinase 1 (CDC2) by phosphorylation at an alternative site (Thr14).

By abrogating the DNA damage checkpoint via blockade of Wee1 activity in WiDr cells bearing mutated p53, MK-1775 treatment inhibits the basal phosphorylation of CDC2 at Tyr15 (CDC2Y15) with EC50 of 49 Nuevo Méjico, and suppresses gemcitabine-, carboplatin- or cisplatin-induced phosphorylation of CDC2 and cell cycle arrest in a dose-dependent manner, with EC50 of 82 nM and 81 Nuevo Méjico, 180 nM and 163 Nuevo Méjico, as well as 159 nM and 160 Nuevo Méjico, respectively. MK-1775 treatment alone at 30-100 nM has no significant antiproliferative effect in WiDr and H1299 cells, whereas MK-1775 at 300 Nuevo Méjico, sufficient to inhibit Wee1 by >80%, displays moderate but significant antiproliferative effects by 34.1% in WiDr cells and 28.4% in H1299 cells.