Description
PD 407824 is an inhibitor of the checkpoint kinases Chk1 and WEE1 (IC
50s = 47 and 97 nM, respectively). It is selective for Chk1 and WEE1 over PKC (IC
50 = 3.4 μM), Cdk4 (IC
50 = 3.75 μM), as well as c-Src and the PDGF and FGF receptors (IC
50s = >50 μM for all), and other Cdks (IC
50s = >50 μM). PD 407824 sensitizes SK-OV-3 and OVCAR-3 ovarian cancer cells, as well as cisplatin-resistant A2780cis cells, to cisplatin when used at a concentration of 0.5 μM. It also sensitizes C2C12 myoblasts to bone morphogenic protein 4 (BMP4) and, when used in combination with BMP4, inhibits myotube formation and induces myoblasts to differentiate into mature osteoblasts. PD 407824, in combination with BMP4, induces human embryonic stem cells to differentiate into cells with mesoderm or cytotrophoblast stem cell lineages.
Uses
PD-407824 has been used as a wee-1 inhibitor to study its effects on
Xenopus laevis embryos. It has also been used as a checkpoint-1 (Chk-1) inhibitor to study its effects on the sensitivity of head and neck squamous carcinoma cells to gemcitabine.
Uses
PD-407824 is a Wee1/Chk1 inhibitor useful as cancer treatments.
Biological Activity
Selective inhibitor of checkpoint kinases Chk1 and Wee1 (IC 50 values are 47 and 97 nM respectively). Displays selectivity over a range of other protein kinases; IC 50 values are 3.4, 3.75, > 5, > 50, > 50 and > 50 μ M for PKC, CDK4, other CDKs, c-Src, PDGFR and FGFR respectively.
Biochem/physiol Actions
PD-407824 is a Wee1/Chk1 inhibitor.
References
[1] JEFF B. SMAILL . Synthesis and structure–activity relationships of N-6 substituted analogues of 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of Wee1 and Chk1 checkpoint kinases[J]. European Journal of Medicinal Chemistry, 2008, 43 6: Pages 1276-1296. DOI:
10.1016/j.ejmech.2007.07.016[2] BRIAN D. PALMER. 4-Phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione Inhibitors of the Checkpoint Kinase Wee1. StructureActivity Relationships for Chromophore Modification and Phenyl Ring Substitution[J]. Journal of Medicinal Chemistry, 2006, 49 16: 4896-4911. DOI:
10.1021/jm0512591[3] SHILPI ARORA . RNAi screening of the kinome identifies modulators of cisplatin response in ovarian cancer cells[J]. Gynecologic oncology, 2010, 118 3: Pages 220-227. DOI:
10.1016/j.ygyno.2010.05.006[4] LINGLING FENG. Discovery of a Small-Molecule BMP Sensitizer for Human Embryonic Stem Cell Differentiation.[J]. Cell reports, 2016, 15 9: 2063-2075. DOI:
10.1016/j.celrep.2016.04.066
