5-[(2,3-difluoro-6-Methoxyphenyl)carbonyl]-2-N-(1-Methanesulfonylpiperidin-4-yl)pyriMidine-2,4-diaMine
R547
CAS: 741713-40-6
Molecular Formula: C18H21F2N5O4S
5-[(2,3-difluoro-6-Methoxyphenyl)carbonyl]-2-N-(1-Methanesulfonylpiperidin-4-yl)pyriMidine-2,4-diaMine - Names and Identifiers
5-[(2,3-difluoro-6-Methoxyphenyl)carbonyl]-2-N-(1-Methanesulfonylpiperidin-4-yl)pyriMidine-2,4-diaMine - Physico-chemical Properties
| Molecular Formula | C18H21F2N5O4S |
| Molar Mass | 441.45 |
| Density | 1.49 |
| Boling Point | 703.7±70.0 °C(Predicted) |
| pKa | 4.22±0.10(Predicted) |
| Storage Condition | -20℃ |
| Use | R547 is an effective, ATP competitive CDK1/2/4 inhibitor with a Ki of 2 nM/3 nM/1 nM, which has a slightly weaker effect on CDK7 and GSK3α/β, while inhibiting other kinase activities. Phase 1. |
| In vitro study | R547 was identified as a diaminopyrimidine compound and is a potent and selective atp competitive CDK inhibitor. R547 potently inhibits CDK1/cyclinB, CDK2/cyclinE and CDK4/cyclinD1(Ki = 1-3nm) and is inactive against a panel of> 120 unrelated kinases (Ki> 5000 nm). R547 effectively inhibits the proliferation of drug-resistant tumor cell lines independently of histological type, retinoblastoma protein, or p53 status with IC50s <0.60 μm. R547 reduces the level of phosphorylation of a cellular retinoblastoma protein at a specific CDK phosphorylation site at the same concentration that induces cell cycle arrest, this suggests that R547 may be a pharmacokinetic marker for clinical use. R547 inhibited the proliferation of tumor cell lines and was active in all 19 tested cell lines regardless of tissue origin, multidrug resistance (MDR), p53 or retinoblastoma status. R547 possesses two 5 and 6-fluoro substitutions ultimately with a lower single-digit molar potency of the inhibitor to CDKs (Ki = 0.001, 0.003, and μm CDK1, CDK2, to, respectively) and excellent cell strength (IC50=0.08 μm HCT116 cell line). R547, a diaminopyrimidine compound, is a potent and selective ATP competitive CDK inhibitor. R547 potently inhibits CDK1/cyclinB,CDK2/cyclinE, and CDK4/cyclinD1(Ki = 1-3nm), while having no activity on more than 120 unrelated kinases (Ki> nm). R547 potently inhibits the proliferation of tumor cell lines and, independent of multidrug resistance status, histological type, retinoblastoma protein, or p53 status, has an IC50 S <0.60 μm. R547, at the same concentration that induces cell cycle arrest, reduces the phosphorylation of intracellular retinoblastoma proteins at specific CDK phosphorylation sites, showing potential pharmacokinetic markers for clinical use. R547 inhibited proliferation of tumor cell lines and was effective against all 19 cell lines tested, independent of tissue origin, multidrug resistance (MDR),p53, or retinoblastoma status. R547 has 5-fluoro and 6-fluoro substituents for CDKs (Ki 0.001,0.003, and 0.001 μm for CDK1,CDK2, and CDK4, respectively) it had low single-digit nanomolar inhibitory potency and excellent intracellular potency (IC50=0.08 μm, HCT116 cell line). |
| In vivo study | R547, at an oral dose of 40 mg/kg per day, showed significant TGI in colon, lung, breast, prostate and melanoma human tumor xenograft models (79-99%). R547 was equally effective (TGI, 61-95%) when administered at a dose of 40 mg/kg intravenously once a week. These doses of R547 were non-toxic and did not result in weight loss. Over the course of the 3-week study, R547 showed no significant signs of toxicity and no gross pathological changes were found at necropsy at the end of the study. In the HCT116 human colorectal tumor xenograft nude mouse model, R547 inhibited tumor growth by up to 95%. R547 elicited significant TGI in all tested models when the oral and intravenous doses were at or below the maximum tolerated dose. R547 inhibits the phosphorylation of tumor retinoblastoma protein under the effective exposure of tumor xenograft model, providing a pharmacodynamic biomarker for clinical application. The R547 molecule reported here suggests that it is a promising molecule for the evaluation of solid tumor therapy. R547 has significant inhibitory activity (P < 0.01) against a variety of mature human tumors administered in oral and intravenous doses. R547, administered orally at a dose of 40 mg/kg per day, exhibited significant TGI in human tumor xenograft models of colon, lung, breast, prostate, and melanoma (79-99%). R547 was equally effective at a once-weekly dose of 40 mg/kg I. v. (TGI,61-95%). These doses of R547 were not toxic and did not cause weight loss. During the 3-week study period, R547 did not exhibit significant signs of toxicity and did not have any overt pathology at the end of the study necropsy. In the HCT116 human colon tumor xenograft nude mouse model, R547 inhibited tumor growth by up to 95%. R547 elicited significant TGI in all tested models when dosed orally or intravenously at or below the maximum tolerated dose. The effective exposure of R547 to tumor xenograft model will inhibit the phosphorylation of retinoblastoma protein, which provides a pharmacodynamic biological index for clinical application. These reports indicate that R547 is a promising molecule for the treatment of solid tumors. |
5-[(2,3-difluoro-6-Methoxyphenyl)carbonyl]-2-N-(1-Methanesulfonylpiperidin-4-yl)pyriMidine-2,4-diaMine - Preparation solution concentration reference
| 1mg | 5mg | 10mg | |
|---|---|---|---|
| 1 mM | 2.265 ml | 11.326 ml | 22.653 ml |
| 5 mM | 0.453 ml | 2.265 ml | 4.531 ml |
| 10 mM | 0.227 ml | 1.133 ml | 2.265 ml |
| 5 mM | 0.045 ml | 0.227 ml | 0.453 ml |
Last Update：2024-01-02 23:10:35
5-[(2,3-difluoro-6-Methoxyphenyl)carbonyl]-2-N-(1-Methanesulfonylpiperidin-4-yl)pyriMidine-2,4-diaMine - Reference Information
| biological activity | R547 is an effective, ATP competitive CDK1/2/4 inhibitor, Ki is 2 nM/3 nM/1 nM, which has a slightly weaker effect on CDK7 and GSK3α/β, while inhibiting other kinase activities. Phase 1. R547 (Ro 4584820) is an effective, ATP competitive CDK1/2/4 inhibitor with a Ki of 2 nM/3 nM/1 nM, which has a slightly weaker effect on CDK7 and GSK3α/β, while inhibiting other kinase activities. Phase 1. |
| in vitro study | R547 was identified as a diaminopyrimidine compound, a potent selective atp competitive CDK inhibitor. R547 can effectively inhibit CDK1/cyclinB, CDK2/cyclinE and CDK4/cyclinD1(Ki = 1-3nM), and has no activity against a group of> 120 unrelated kinases (Ki> 5000 nm). R547 effectively inhibits the proliferation of drug-resistant tumor cell lines, histological type, retinoblastoma protein, or p53 status with IC50s <0.60 μM. R547 can reduce the phosphorylation level of cell retinoblastoma protein at a specific CDK phosphorylation site, and its phosphorylation level is the same as the concentration that induces cell cycle arrest, which indicates that R547 may be a clinical application Pharmacokinetic marker. R547 inhibits the proliferation of tumor cell lines and is active in all 19 tested cell lines, regardless of tissue origin, multidrug resistance (MDR), p53 or retinoblastoma status. R547 has two 5 and 6-fluoro replacements with a lower inhibitor, single-digit molar efficacy against CDKs (Ki = 0.001, 0.003, and 0.001 μM CDK1, CDK2, to, respectively) and excellent cell strength (IC50=0.08 μM HCT116 cell line). R547 is a diaminopyrimidine compound, which is an effective selective ATP competitive CDK inhibitor. R547 effectively inhibited CDK1/cyclinB,CDK2/cyclinE, and CDK4/cyclinD1(Ki = 1-3nM), but had no activity against more than 120 unrelated kinases (Ki>5,000nM). R547 effectively inhibits the proliferation of tumor cell lines and is independent of multi-drug resistance status, histological type, retinoblastoma protein, or p53 status, IC50s <0.60 μM. At the same concentration that induces cell cycle arrest, R547 reduces the phosphorylation of intracellular retinoblastoma protein at a specific CDK phosphorylation site, showing a potential pharmacokinetic marker for clinical application. R547 inhibited the proliferation of tumor cell lines and was not affected by tissue origin, multidrug resistance (MDR),p53, or retinoblastoma status, and was effective against all 19 cell lines tested. R547 has 5-fluorine and 6-fluorine substituents, has low single-digit nanomolar inhibitory efficacy against CDKs (Ki for CDK1,CDK2, and CDK4 is 0.001,0.003, and 0.001 μM, respectively), and has excellent intracellular efficacy (IC50=0.08 μM,HCT116 cell line). |
| in vivo study | R547 oral dose is 40 mg/kg per day, which shows significant TGI(79-99%) in xenograft models of colon, lung, breast, prostate and melanoma human tumors. R547 is equally effective (TGI, 61-95%) when the dose is 40 mg/kg intravenously once a week. These doses of R547 were non-toxic and did not result in weight loss. During the 3-week study, R547 showed no obvious signs of toxicity, and no gross pathological changes were found at autopsy at the end of the study. In the HCT116 human colorectal tumor xenograft nude mouse model, R547 inhibits tumor growth up to 95%. R547 induced significant TGI in all models tested when oral and intravenous doses were at or below the maximum tolerated dose. R547 inhibits phosphorylation of tumor retinoblastoma protein under effective exposure of tumor xenograft model, providing a pharmacodynamic biomarker for clinical application. The R547 molecule reported in this paper suggests that this molecule is a promising molecule for evaluating solid tumor therapy. R547 has significant inhibitory activity on various mature human tumors (P < 0.01) when administered orally and intravenously. R547 was administered orally at a dose of 40 mg/kg per day and showed significant TGI(79-99%) in colon cancer, lung cancer, breast cancer, prostate cancer, and melanoma human tumor xenograft models. R547 is equally effective when administered at a weekly dose of 40 mg/kg I. v. (TGI,61-95%). These doses of R547 were not toxic and did not cause weight loss. During the 3-week study period, R547 did not show significant toxicity signals, and there was no obvious pathology at the autopsy at the end of the study. In a nude mouse model of HCT116 human colon tumor xenograft, R547 inhibits tumor growth up to 95%. When R547 was administered orally or intravenously at or below the maximum tolerated dose, it caused significant TGI in all test models. The effective exposure of R547 to tumor xenograft model can inhibit the phosphorylation of retinoblastoma protein in tumors, which provides a pharmacodynamic biological indicator for clinical application. These reports suggest that R547 is a promising molecule for the treatment of solid tumors. |
| target | TargetValue CDK4/CyclinD1 (Cell-Free Assay) 1 nM(Ki) CDK1/CyclinB (Cell-Free Assay) 2 nM(Ki) CDK2/CyclinE (Cell-Free Assay) 3 nM(Ki) |
| Target | Value |
| CDK4/CyclinD1 (Cell-free assay) | 1 nM(Ki) |
| CDK1/CyclinB (Cell-free assay) | 2 nM(Ki) |
| CDK2/CyclinE (Cell-free assay) | 3 nM(Ki) |
Last Update：2024-04-09 20:45:29
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CAS: 741713-40-6
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