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SCH900776

Description of SCH900776: SCH900776 is an agent targeting cell cycle checkpoint kinase 1 (Chk1) with potential radiosensitization and chemosensitization activities. Chk1 inhibitor SCH 900776 specifically binds to and inhibits Chk1, which may result in tumor cells bypassing Chk1-dependent cell cycle arrest in the S and G2/M phases to undergo DNA repair prior to entry into mitosis; tumor cells may thus be sensitized to the DNA-damaging effects of ionizing radiation and alkylating chemotherapeutic agents. Chk1 is an ATP-dependent serine-threonine kinase that in response to DNA damage phosphorylates cdc25 phosphatases, resulting in inhibitory tyrosine phosphorylation of CDK-cyclin complexes and cell cycle arrest. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

Current developer:    Schering-Plough/Merck.

Preclinical study of SCH900776:  SCH900776 reduced the growth-inhibitory concentration of hydroxyurea by 20-70 fold. A similar magnitude of sensitization was observed with cytarabine, a 5-10 fold sensitization occurred with gemcitabine, but no sensitization occurred with cisplatin, 5-fluorouracil or 6-thioguanine. Sensitization occurred at hydroxyurea concentrations that marginally slowed DNA replication without apparent activation of Chk1, but this led to dependence on Chk1 that increased with time. For example, when added 18 h after hydroxyurea, SCH900776 induced DNA double-strand breaks consistent with rapid collapse of replication forks. In addition, some cell lines were highly sensitive to SCH900776 alone, and these cells required lower concentrations of SCH900776 to sensitize them to hydroxyurea. We conclude that some tumors may be very sensitive to the combination of SCH900776 and hydroxyurea. Delayed administration of SCH900776 may be more effective than concurrent treatment. SCH900776 is currently in Phase I clinical trials, and these results provide the rationale and schedule for future clinical trials. (source: Mol Cancer Ther. 2011 Dec 27. [Epub ahead of print])

Activity of SCH900776: SCH 900776 was identified as a highly potent and functionally optimal CHK1 inhibitor with minimal intrinsic antagonistic properties. SCH 900776 exposure phenocopies short interfering RNA-mediated CHK1 ablation and interacts synergistically with DNA antimetabolite agents in vitro and in vivo to selectively induce dsDNA breaks and cell death in tumor cell backgrounds.

Bioactivity of SCH900776:

 IC50(CHK1) = 0.003 µmol/L

IC50(CDK2) = 0.16 µmol/L

IC50(CHK2) = 1.5 µmol/L

EC50 = ~ 0.1 µmol/L.

(Source: Mol Cancer Ther. 2011 Apr;10(4):591-602.).

1: Guzi TJ, Paruch K, Dwyer MP, Labroli M, Shanahan F, Davis N, Taricani L, Wiswell D, Seghezzi W, Penaflor E, Bhagwat B, Wang W, Gu D, Hsieh Y, Lee S, Liu, M, Parry D. Targeting the replication checkpoint using SCH 900776, a potent and functionally selective CHK1 inhibitor identified via high content screening. Mol  Cancer Ther. 2011 Apr;10(4):591-602.

2. Guzi, Timothy J.; Parry, David A.; Labroli, Marc A.; Dwyer, Michael P.; Paruch, Kamil; Rosner, Kristen E.; Shen, Ruichao; Popovici-Muller, Janeta.  Preparation of pyrimidine nucleoside analogs as modulators of cell cycle checkpoints and their use in combination with checkpoint kinase inhibitors. PCT Int. Appl. (2009), WO 2009061781.

3. Guzi, Timothy J.; Paruch, Kamil; Dwyer, Michael P.; Labroli, Marc; Keertikar, Kartik M. Preparation of pyrazolopyrimidines as cyclin-dependent kinase inhibitors. PCT Int. Appl. (2008), WO 2008130569.

4. Guzi, Timothy J.; Paruch, Kamil; Dwyer, Michael P.; Labroli, Marc; Keertikar, Kartik M. Preparation of pyrazolopyrimidines as cyclin-dependent kinase inhibitors.  U.S. Pat. Appl. Publ. (2007), US 20070281951.

5. Guzi, Timothy J.; Paruch, Kamil; Dwyer, Michael P.; Parry, David A. Pyrazolo[1,5-a]pyrimidine compounds as protein kinase inhibitors and their preparation, pharmaceutical compositions and their use in the treatment of protein kinase-mediated diseases. U.S. Pat. Appl. Publ. (2007), US 20070082900.

6. Guzi, Timothy J.; Paruch, Kamil; Dwyer, Michael P.; Labroli, Marc; Keertikar, Kartik M. Preparation of pyrazolopyrimidines as cyclin-dependent kinase inhibitors, U.S. Pat. Appl. Publ. (2006), US 20060128725.

7. Dwyer MP, Paruch K, Alvarez C, Doll RJ, Keertikar K, Duca J, et al. Versatile templates for the development of novel kinase inhibitors: discovery of novel CDK inhibitors. Bioorg Med Chem Lett 2007;17: 6216–9.

8. Paruch K, Dwyer MP, Alvarez C, Brown C, Chan TY, Doll RJ, et al. Discovery of dinaciclib (SCH 727965): a potent and selective inhibitor of cyclin-dependent kinases. ACS Med Chem Lett 2010;1:204–8.

9. Dwyer M, Paruch K, Labroli M, Alvarez C, Keertikar K, Poker C, et al. Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: A template-based approach – part 1. Bioorgan. & Med. Chem.Lett. 2011, 21(1): 467-470.

10. Labroli M, Dwyer MP, Paruch K, Dwyer MP, Alvarez C, Keertikar K, et al. Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: A template-based approach – part 2.  Bioorgan. & Med. Chem.Lett. 2011, 21(1):471-474.  Available from: http://dx.doi.org/10.1016/j.bmcl.2010.10.11.