AstraZeneca has licensed a drug which is in mid-stage studies for ovarian cancer from Merck & Co.
The pact centres around the US drug major’s MK-1775, an oral small molecule inhibitor of WEE1 kinase, a cell cycle checkpoint protein regulator. Preclinical data indicate that disruption of WEE1 may enhance the cell killing effects of some anticancer agents and the compound is in Phase IIa studies in combination with standard of care therapies for the treatment of patients with certain types of ovarian cancer………….read all at
http://www.pharmatimes.com/Article/13-09-11/AZ_pays_50_million_upfront_for_Merck_Co_cancer_drug.aspx
MK-1775
MK-1775 is a potent and selective Wee1 inhibitor with IC50 of 5.2 nM; hinders G2 DNA damage checkpoint. Phase 2. IC50 of 5.2 nM
Chemical Name: 1,2-dihydro-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-2-(2-propen-1-yl)-3H-Pyrazolo[3,4-d]pyrimidin-3-one
Elemental Analysis: C, 64.78; H, 6.44; N, 22.38; O, 6.39
CAS 955365-80-7
C27H32N8O2
MW 500.61
| Biological Activity: |
A potent and selective Wee1 kinase inhibitor in vitro and in vivo.
MK 1775 abolishes cyclin-dependent kinase 1 (CDC2) activity by phosphorylation of the Tyr15 residue. It abrogates a DNA damage checkpoint (G2-phase), leading to apoptosis in combination with several DNA-damaging agents selectively in p53-deficient tumor cell lines. It is under clinical trial for advanced solid tumors.
References:
H. Hirai et al. Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents. Mol. Cancer. Ther. 2009, 8(11), 2992-3000. [online]
S. Schellens et al. A Phase I and pharmacological study of MK-1775, a Wee1 tyrosine kinase inhibitor, in both monotherapy and in combination with gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumors. J. Clin. Oncol. 2009, 27(15s), abstr 3510.
H. Hirai et al. MK-1775, a small molecule Wee1 inhibitor, enhances anti-tumor efficacy of various DNA-damaging agents, including 5-fluorouracil. Cancer Biol. Ther. 2010, 9(7), 523-525. [online]
CC Porter et al. Integrated genomic analyses identify WEE1 as a critical mediator of cell fate and a novel therapeutic target in acute myeloid leukemia. Leukemia 2012, 26, 1266-1276. [online]
MK-1775 is an inhibitor of Wee1, a kinase that phosphorylates CDC2 to inactivate the CDC2/cyclin B complex (regulating the G2 checkpoint). Since most human cancers harbor p53-dependent G1 checkpoint abnormalities, they are dependent on the G2 checkpoint. G2 checkpoint abrogation may therefore sensitize p53 deficient tumor cells to anti-cancer agents
MK-1775 inhibits phosphorylation of CDC2 at Tyr15 (CDC2Y15), a direct substrate of Wee1 kinase in cells. MK-1775 abrogates G2 DNA damage checkpoint, leading to apoptosis in combination with DNA-damaging chemotherapeutic agents such as gemcitabine, carboplatin, and cisplatin selectively in p53-deficient cells. In vivo, MK-1775 potentiates tumor growth inhibition by these agents, and cotreatment does not significantly increase toxicity. The enhancement of antitumor effect by MK-1775 was well correlated with inhibition of CDC2Y15 phosphorylation in tumor tissue and skin hair follicles. Our data indicate that Wee1 inhibition provides a new approach for treatment of multiple human malignancies. [Mol Cancer Ther 2009;8(11):2992-3000].
MK-1775 is a first in class Wee1 inhibitor that is well tolerated and shows promising anti-tumor activity in previously treated pts. for detail see: http://meeting.ascopubs.org/cgi/content/abstract/27/15S/3510.
