PD 407824 (hydrate)

PD 407824 is an inhibitor of the checkpoint kinases Chk1 and WEE1 (IC₅₀s = 47 and 97 nM, respectively).¹ It is selective for Chk1 and WEE1 over PKC (IC₅₀ = 3.4 µM) and Cdk4 (IC₅₀ = 3.75 µM), as well as c-Src and the PDGF and FGF receptors (IC₅₀s = >50 µM for all), and other CDKs (IC₅₀s = >50 µM).² PD 407824 sensitizes SKOV3 and OVCAR-3 ovarian cancer cells, as well as cisplatin-resistant A2780cis cells, to cisplatin when used at a concentration of 0.5 µM.³ It also sensitizes C2C12 myoblasts to bone morphogenetic protein 4 (BMP4) and, when used in combination with BMP4, inhibits myotube formation and induces myoblasts to differentiate into mature osteoblasts.⁴ PD 407824, in combination with BMP4, induces human embryonic stem cells (hESCs) to differentiate into cells with mesoderm or cytotrophoblast stem cell lineages.

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1. Smaill, J.B., Baker, E.N., Booth, R.J., et al. 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. Eur. J. Med. Chem. 43(6), 1276-1296 (2008).

2. Palmer, B.D., Thompson, A.M., Booth, R.J., et al. 4-Phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione inhibitors of the checkpoint kinase Wee1. Structure-activity relationships for chromophore modification and phenyl ring substitution. J. Med. Chem. 49(16), 4896-4911 (2006).

3. Arora, S., Bisanz, K.M., Peralta, L.A., et al. RNAi screening of the kinome identifies modulators of cisplatin response in ovarian cancer cells. Gynecol. Oncol. 118(3), 220-227 (2010).

4. Feng, L., Cook, B., Tsai, S.-Y., et al. Discovery of a small-molecule BMP sensitizer for human embryonic stem cell differentiation. Cell Rep. 15(9), 2063-2075 (2016).