PHA-767491 hydrochloride

• CAT Number: I005601
• CAS Number: 942425-68-5
• Molecular Formula: C12H11N3O.HCl
• Molecular Weight: 249.7
• Purity: ≥95%
• Synonyms: PHA767491 hydrochloride; PHA-767491 hcl
• Target: Cdc7/CDK9
• Solubility: DMSO: ＜ 9 mg/mL
• Storage: 3 years -20C powder
• IC50: 10 nM(Cdc7); 34 nM(Cdk9) Target: Cdc7/CDK9

PHA-767491 (CAY10572) Hcl is a potent, ATP-competitive dual Cdc7/Cdk9 inhibitor with IC50 values of 10/34 nM. 


in vitro: PHA-767491 displays approximately 20-fold selectivity for Cdk1, Cdk2 and GSK3-β, 50-fold selectivity for MK2 and Cdk5 and 100-fold selectivity for PLK1 and CHK2. PHA-767491 inhibits cell proliferation in a variety of human cell lines with IC50 of 0.86 μM for SF-268 to 5.87 μM for K562, and significantly induces apoptosis in a p53-independent manner in almost all cell lines in contrast with 5-FU or gemcitabine which only works in a few of cell lines. Unlike current DNA synthesis inhibitors, PHA-767491 treatment at 5 μM blocks the initiation of DNA replication but not replication fork progression, due to specific inhibition of Cdc7 kinase and Mcm2 phosphorylation at the Cdc7-dependent Ser40 site. The direct mitochondrial dependent pro-apoptosis effect of PHA-767491 is also observed when applied at 1 μM in quiescent chronic lymphocytic leukemia (CLL) cells through the similar mechanism with EC50 of 0.34-0.97 μM. While in proliferating CLL cells stimulated by CD154 and interleukin-4, PHA-767491 treatment at 5 μM abolishes DNA synthesis by inhibiting Cdc7 rather than triggering cell death. The up-regulated Mcl-1 levels in ABT-737-resistant OCI-LY1 and SU-DHL-4 cells can be significantly decreased by PHA-767491 treatment at 3 μM possibly due to the inhibition of Cdk9, leading to the restoration of the sensitivity to ABT-737.


in vivo: Administration of PHA-767491 twice a day for 5 days significantly inhibits the growth of HL60 xenograft in a dose-dependent manner with TGI of 50% and 92% at dose of 20 mg/kg and 30 mg/kg, respectively, the effect of which is also marked in A2780, Mx-1, and HCT-116 xenograft models as well as the DMBA-induced mammary carcinomas, and correlates with Cdc7 inhibition and subsequently decreased phosphorylation of Mcm2 at the Cdc7-dependent site Ser40.

Reference

[1]. Natoni, Alessandro; Murillo, Laura S.; Kliszczak, Anna E. et al. Mechanisms of Action of a Dual Cdc7/Cdk9 Kinase Inhibitor against Quiescent and Proliferating CLL Cells. Molecular Cancer Therapeutics (2011), 10(9), 1624-1634. 


[2]. Swords R, Mahalingam D, O/’Dwyer M, et al. Cdc7 kinase – a new target for drug development. Eur J Cancer. 2010 Jan;46(1):33-40. doi: 10.1016/j.ejca.2009.09.020. 


[3]. Montagnoli A, Moll J, Colotta F. Targeting cell division cycle 7 kinase: a new approach for cancer therapy. Clin Cancer Res. 2010 Sep 15;16(18):4503-8. doi: 10.1158/1078-0432.CCR-10-0185. Epub 2010 Jul 20. 


[4]. Montagnoli A, Valsasina B, Croci V, et al. A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity. Nat Chem Biol. 2008 Jun;4(6):357-65. doi: 10.1038/nchembio.90.