| 名稱 | Riviciclib hydrochloride |
| 描述 | Riviciclib hydrochloride (P276-00) is a novel CDK1, CDK4 and CDK9 inhibitor with IC50 of 79 nM, 63 nM and 20 nM, respectively. Phase 2/3. |
| 細(xì)胞實(shí)驗(yàn) | The cells are seeded at a density of 3,000-5,000 cells per well, depending on cell type in 180 μL of culture medium in 96-well plate and incubated overnight to allow the cells to adhere. Varying concentrations of compounds are added to the wells and incubated for 48 h at 37°C. 3H-thymidine (0.25 μCi) is added to each well, and incorporation of the radiolabel is allowed to proceed for 5 to 7 h. Following this incubation, cells are harvested onto GF/B unifilter plates using a Packard Filtermate Universal harvester, and the plates are counted in a Packard Top Count 96-well liquid scintillation counter. (Only for Reference) |
| 激酶實(shí)驗(yàn) | Cdk4-D1/Cdk2-E enzyme assay: The Cdk4-D1/Cdk2-E enzyme assay is run in 96-well format using Millipore Multiscreen filtration plates. All assay steps are done in a single filter plate. The filtration wells are prewetted with 100 μL of kinase buffer [50 mmol/L HEPES (pH, 7.5), 10 mmol/L MgCl2, 1 mmol/L EGTA], and then the solution is removed by vacuum. With filter plate on vacuum manifold, 50 μL GST-Rb bound to GSH-Sepharose beads in kinase buffer (0.5 μg GST-Rb/50 μL) is added to each well, and vacuum is applied to the filter plate. About 25 μL of a reaction mix containing ATP (cold + hot) and 4× phosphatase inhibitor mix (40 μMol/L unlabeled ATP, 10 μCi/mL γ32P-ATP, 40 mmol/L h-glycerophosphate, 4 mmol/L DTT, 0.4 mmol/L NaF, 0.4 mmol/L sodium orthovanadate) diluted in kinase buffer is added to each well. The test compound (4×final concentration in kinase buffer) or kinase buffer alone (control) is then added in an additional 25 μL volume. To each well, 50 μL (100 ng) of human Cdk4-D1/Cdk2-E enzyme in kinase buffer is added to initiate the reaction, which is allowed to continue for 30 min at 30°C. When the reaction is completed, vacuum is applied again, and the plate is washed with the TNEN buffer [20 mmol/L Tris (pH, 8.0), 100 mmol/L NaCl, 1 mmol/L EDTA, 0.5% nonidet-P40] thrice; the filter plate is air-dried and is placed in a Multiscreen adapter plate. Packard Microscint-O cocktail (30 μL) is added, and the plate is covered with a Top-Seal A film. Quantitation of 32P-GST-Rb in 96-well filter plates is carried out by Top Count scintillation counter. All compounds are tested initially at 1 μMol/L concentration. Compounds showing more than or equal to 50% inhibition are further profiled for IC50 determination. |
| 體外活性 | Riviciclib對(duì)Cdk4-D1顯示出比對(duì)Cdk2-E[1]高40倍的選擇性。它對(duì)多種人類癌癥細(xì)胞系展現(xiàn)出強(qiáng)大的抗增殖效果，包括HCT-116、U2OS、H-460、HL-60、HT-29、SiHa、MCF-7、Colo-205、SW-480、PC-3、Caco2、T-24，其IC50范圍從300到800 nmol/L，且相較于正常成纖維細(xì)胞，對(duì)癌細(xì)胞顯示出高度的選擇性[1]。Riviciclib能以與ATP競(jìng)爭(zhēng)的方式下調(diào)cyclin D1和Cdk4，并減少Cdk4特異性的pRb Ser780磷酸化。Riviciclib還通過激活細(xì)胞caspase-3活性和DNA階梯形成誘導(dǎo)凋亡[1]。 |
| 體內(nèi)活性 | Riviciclib通過腹膜注射給藥方式，每日50 mg/kg，連續(xù)治療20次，可顯著抑制小鼠結(jié)腸癌(CA-51)的生長(zhǎng)。然而，在小鼠肺癌模型(Lewis lung)中，通過每隔一天腹膜注射60 mg/kg（每日兩次，每次30 mg/kg），共治療7次，也顯示出顯著的生長(zhǎng)抑制效果[2]。此外，Riviciclib還能抑制人類結(jié)腸癌HCT-116異種移植物和人類非小細(xì)胞肺癌H-460異種移植物的生長(zhǎng)[2]。有效性研究表明，其最大耐受劑量為78 mg/kg/d[2]。 |
| 存儲(chǔ)條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | Ethanol : 7 mg/mL (15.97 mM)
DMSO : 82 mg/mL (187.1 mM)
H2O : 81 mg/mL (184.8 mM)
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| 關(guān)鍵字 | inhibit | Inhibitor | Riviciclib | CDK | Riviciclib hydrochloride | Riviciclib Hydrochloride | Cyclin dependent kinase | Apoptosis |
| 相關(guān)產(chǎn)品 | L-Glutamic acid | Metronidazole | 5-Fluorouracil | Dextran sulfate sodium salt (MW 4500-5500) | Stavudine | Tributyrin | Myricetin | Sorafenib | L-Ascorbic acid | Acetylcysteine | Salicylic acid | Sodium 4-phenylbutyrate |
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