Background:

R547 is a novel, selective inhibitor of cell cycle and transcriptional cyclin dependent kinases with a Ki of median 2 nM for CDK1/cyclin B, CDK2/cyclin E, and CDK4/cyclin D1((Ki=0.001,0.003,and 0.001 μM for CDK1,CDK2, and CDK4,respectively).[1]
Cyclin-dependent kinases (CDKs) are a family of protein kinases regulating the cell cycle, transcription, mRNA processing, and the differentiation of nerve cells which considered a potential anticancer target. CDK inhibitors such as Seliciclib are undergoing clinical trials. Although it was originally developed as a potential anti-cancer drug, in recent laboratory tests Seliciclib has also proven to induce apoptosis in neutrophil granulocytes, which mediate inflammation.[2].
R547 inhibited the proliferation of tumor cell lines and is active in all 19 cell lines tested irrespective of tissue of origin, multidrug resistance (MDR), p53, or retinoblastoma status. R547 possessing both 5-and 6-fluoro substitution culminated in an Inhibitor with low, single-digit nanomolar potency against the CDKs and excellent cellular potency (IC50=0.08 μM,HCT116 cell line). R547 administered orally at dose of 40 mg/kg daily in colon, lung, breast, prostate, and melanoma human tumor xenograft models shows significant TGI (79-99%). R547 is equally efficacious (TGI, 61-95%) when dosed with 40 mg/kg i.v. once weekly. These doses of R547 are not toxic and did not result in body weight loss. R547 does not show signs of overt toxicity during the course of the 3-week study and any gross pathology at necropsies done at the end of the studies. [3]R547 inhibits tumor growth up to 95% in the HCT116 human colorectal tumor xenograft model in nude mice . R547 causes significant TGI in all of the models tested when dosed orally and i.v. at or below the maximum tolerated dose. R547 inhibits phosphorylation of retinoblastoma protein in tumors at the efficacious exposures in tumor xenograft models, providing a pharmacodynamic biomarker for clinical use. R547 reported here suggests that this is a promising molecule for evaluation in the treatment of solid tumors. [4]
参考文献:
1. Davis MI1, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. “Comprehensive analysis of kinase inhibitor selectivity.” Nat Biotechnol. 2011, 29(11):1046-51.
2. Rossi, Adriano G. “Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis.” 2006. Nature Medicine 12 .
3. Rodriguez A , et al. Mol Cancer Ther, 2006, 5(11), 2644-2658.
4. Chu XJ, et al. J Med Chem, 2006, 49(22), 6549-6560.