741713-40-6 Usage
Description
[4-Amino-2-[(1-methylsulfonylpiperidin-4-yl)amino]pyrimidin-5-yl](2,3-difluoro-6-methoxyphenyl)methanone(R 547), also known as R547, is a potent ATP-competitive inhibitor of cyclin-dependent kinases (CDKs) 1, 2, and 4 with Ki values of 2 nM, 3 nM, and 1 nM, respectively. It is less potent to CDK7 and GSK3α/β and inactive against other kinases. R547 is a diaminopyrimidine compound that targets Cdk1/cyclin B, Cdk2/cyclin E, and Cdk4/cyclin D1, playing a crucial role in cell cycle regulation and cellular transcription. Its inhibition of these CDKs leads to cell cycle arrest, apoptosis, and reduced phosphorylation of the retinoblastoma protein, making it a promising candidate for cancer treatment.
Uses
Used in Pharmaceutical Industry:
R547 is used as an anticancer agent for targeting dysregulated CDKs, which are often associated with the development of cancer. By inhibiting Cdk1/cyclin B, Cdk2/cyclin E, and Cdk4/cyclin D1, R547 effectively suppresses tumor cell proliferation, induces cell cycle arrest at G1 and G2 phases, and promotes apoptosis. This makes R547 a valuable compound in the development of novel cancer therapeutics.
Used in Drug Development Research:
R547 is utilized in drug development research as a potent inhibitor of CDKs, which are critical positive regulators of cell cycle progression and cellular transcription. Its high specificity for CDK1, CDK2, and CDK4, along with its inactivity against a panel of more than 120 unrelated kinases, makes R547 an ideal candidate for studying the role of CDKs in cancer and other diseases. This research can lead to the development of more targeted and effective treatments for various conditions.
Used in Preclinical Cancer Models:
R547 is employed in preclinical cancer models to evaluate its antitumor activity in vivo. It has demonstrated significant antitumor effects in various human tumor xenograft models, providing valuable insights into its potential as a therapeutic agent for cancer treatment. These preclinical studies are essential for understanding the efficacy and safety of R547 before advancing to clinical trials.
In vitro
R547 identified as a diaminopyrimidine compound, which is a potent and selective ATP-competitive CDK inhibitor. R547 effectively inhibits CDK1/cyclinB, CDK2/cyclinE, and CDK4/cyclinD1(Ki=1-3nM) and is inactive(Ki>5,000nM) against a panel of >120 unrelated kinases. R547 effectively inhibits the proliferation of tumor cell lines independent of multidrug resistant status, histologic type, retinoblastoma protein, or p53 status, with IC50s <0.60 μM. R547 reduces phosphorylation of the cellular retinoblastoma protein at specific CDK phosphorylation sites at the same concentrations that induced cell cycle arrest, suggesting a potential pharmaco dynamics marker for clinical use. R547 inhibits 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(Ki=0.001,0.003,and 0.001 μM for CDK1,CDK2, and CDK4,respectively) and excellent cellular potency (IC50=0.08 μM,HCT116 cell line).
In vivo
R547 administered with oral and i.v. dosing in multiple established human tumor significantly inhibits tumor activity(P < 0.01). 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.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.
Check Digit Verification of cas no
The CAS Registry Mumber 741713-40-6 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 7,4,1,7,1 and 3 respectively; the second part has 2 digits, 4 and 0 respectively.
Calculate Digit Verification of CAS Registry Number 741713-40:
(8*7)+(7*4)+(6*1)+(5*7)+(4*1)+(3*3)+(2*4)+(1*0)=146
146 % 10 = 6
So 741713-40-6 is a valid CAS Registry Number.
InChI:InChI=1/C18H21F2N5O4S/c1-29-13-4-3-12(19)15(20)14(13)16(26)11-9-22-18(24-17(11)21)23-10-5-7-25(8-6-10)30(2,27)28/h3-4,9-10H,5-8H2,1-2H3,(H3,21,22,23,24)
741713-40-6Relevant articles and documents
Discovery of [4-amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5- yl](2,3-difluoro-6-methoxyphenyl)methanone (R547), a potent and selective cyclin-dependent kinase inhibitor with significant in vivo antitumor activity
Chu, Xin-Jie,DePinto, Wanda,Bartkovitz, David,So, Sung-Sau,Vu, Binh T.,Packman, Kathryn,Lukacs, Christine,Ding, Qingjie,Jiang, Nan,Wang, Ka,Goelzer, Petra,Yin, Xuefeng,Smith, Melissa A.,Higgins, Brian X.,Chen, Yingsi,Xiang, Qing,Moliterni, John,Kaplan, Gerald,Graves, Bradford,Lovey, Allen,Fotouhi, Nader
, p. 6549 - 6560 (2007/10/03)
The cyclin-dependent kinases (CDKs) and their cyclin partners are key regulators of the cell cycle. Since deregulation of CDKs is found with high frequency in many human cancer cells, pharmacological inhibition of CDKs with small molecules has the potential to provide an effective strategy for the treatment of cancer. The 2,4-diamino-5-ketopyrimidines 6 reported here represent a novel class of potent and ATP-competitive inhibitors that selectively target the cyclin-dependent kinase family. This diaminopyrimidine core with a substituted 4-piperidine moiety on the C2-amino position and 2-methoxybenzoyl at the C5 position has been identified as the critical structure responsible for the CDK inhibitory activity. Further optimization has led to a good number of analogues that show potent inhibitory activities against CDK1, CDK2, and CDK4 but are inactive against a large panel of serine/threonine and tyrosine kinases (Ki > 10 μM). As one of these representative analogues, compound 39 (R547) has the best CDK inhibitory activities (Ki = 0.001, 0.003, and 0.001 μM for CDK1, CDK2, and CDK4, respectively) and excellent in vitro cellular potency, inhibiting the growth of various human tumor cell lines including an HCT116 cell line (IC50 = 0.08 μM). An X-ray crystal structure of 39 bound to CDK2 has been determined in this study, revealing a binding mode that is consistent with our SAR. Compound 39 demonstrates significant in vivo efficacy in the HCT116 human colorectal tumor xenograft model in nude mice with up to 95% tumor growth inhibition. On the basis of its superior overall profile, 39 was chosen for further evaluation and has progressed into Phase I clinical trial for the treatment of cancer.
