Roniciclib (BAY 1000394)
(Synonyms: BAY 1000394) 目录号 : GC33360
Roniciclib (BAY 1000394) 是一种可口服的泛细胞周期蛋白依赖性激酶 (CDK) 抑制剂，对 CDK1、CDK2、CDK3、CDK4、CDK7 和 CDK9 的 IC50 为 5-25 nM。
Cas No.:1223498-69-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Animal experiment: | Mice[1]Athymic mice bearing established HeLa-MaTu xenograft tumors of approx. 25 mm2 in size are treated orally with Roniciclib (BAY 1000394) at doses of 0.5, 1.0, 1.5, and 2.0 mg/kg once daily for 21 days. Treatment is well tolerated as no body weight loss below the initial body weight is observed. Additional groups of mice are treated on a cyclic intermittent dosing schedule at doses of 1.5, 2.0, and 2.5 mg/kg twice daily for 2 days followed by 5 days without treatment (2 on/5 off). In total, 3 treatment cycles are completed[1]. |
References: [1]. Siemeister G, et al. BAY 1000394, a novel cyclin-dependent kinase inhibitor, with potent antitumor activity in mono- and in combination treatment upon oral application. Mol Cancer Ther. 2012 Oct;11(10):2265-73. | |
Roniciclib is an orally bioavailable pan-cyclin dependent kinase (CDK) inhibitor, with IC50s of 5-25 nM for CDK1, CDK2, CDK3, CDK4, CDK7 and CDK9.
Roniciclib (BAY 1000394) inhibits the kinase activity of the cell-cycle CDKs CDK1/cyclin B, CDK2/cyclin E, and CDK4/cyclinDwith IC50 values of 7, 9, and 11 nM, respectively. The transcriptional CDKs CDK9/cyclin T1 and CDK7/cyclin H/MAT1 are inhibited in a similar range (5 and 25 nM)[1]. Roniciclib potently inhibits the proliferation of various human and murine tumor cell lines with a very balanced profile (mean IC50 on human tumor cells: 16 nM)[2].
Tumor growth is strongly inhibited in a dose-dependent manner with T/C values of 0.19 at the lower dose and of 0.02 (tumor regression) at the higher dose. Furthermore, Roniciclib strongly inhibits growth of HeLa-MaTu tumors that have been grown to a size of approximately 50mm2 before start of treatment (day 8 after inoculation). Treatment with Roniciclib at doses of 1.5 and 1 mg/kg slow tumor growth to T/C values of 0.15 and 0.62, respectively. Addition of Roniciclib to cisplatin result in a strong tumor growth inhibition with T/C values of 0.01 (1.0 mg/kg Roniciclib) and -0.02 (1.5 mg/kg Roniciclib)[1]. Roniciclib has low blood clearance rates in mouse, rat, and dog (0.51, 0.78, and 0.50 Lh-1kg-1, respectively) [2].
[1]. Siemeister G, et al. BAY 1000394, a novel cyclin-dependent kinase inhibitor, with potent antitumor activity in mono- and in combination treatment upon oral application. Mol Cancer Ther. 2012 Oct;11(10):2265-73. [2]. Lücking U, et al. The lab oddity prevails: discovery of pan-CDK inhibitor (R)-S-cyclopropyl-S-(4-{[4-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)sulfoximide (BAY 1000394) for the treatment of cancer. ChemMedChem. 2013 Jul;8(7):1067-85.
| Cas No. | 1223498-69-8 | SDF | |
| 别名 | BAY 1000394 | ||
| Canonical SMILES | C[C@@H](O)[C@H](OC1=NC(NC2=CC=C([S@@](=N)(C3CC3)=O)C=C2)=NC=C1C(F)(F)F)C | ||
| 分子式 | C18H21F3N4O3S | 分子量 | 430.44 |
| 溶解度 | DMSO: ≥ 250 mg/mL (580.80 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.3232 mL | 11.616 mL | 23.232 mL |
| 5 mM | 0.4646 mL | 2.3232 mL | 4.6464 mL |
| 10 mM | 0.2323 mL | 1.1616 mL | 2.3232 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
CDK inhibitors in cancer therapy, an overview of recent development
Am J Cancer Res 2021 May 15;11(5):1913-1935.PMID:34094661doi
Dysregulated cell division, which leads to aberrant cell proliferation, is one of the key hallmarks of cancer. Therefore, therapeutic targets that block cell division would be effective for cancer treatment. Cell division is mainly controlled by a complex composed of cyclin and cyclin dependent kinases (CDKs). To date, the CDK inhibitors (CDKIs), specifically the ones that block the enzyme activity of CDK4 and CDK6 (CDK4/6), have been approved by FDA for the treatment of metastatic hormone receptor positive breast cancer. However, due to the non-selectivity and significant toxicity, most of the first generation CDK inhibitors (so called pan-CDK inhibitors that target several CDKs), have not been approved for clinical application. Despite this, great efforts and progress have been made to enable pan-CDK inhibitors application in the clinical setting. Notably, the development of combination therapy strategies in recent years has made it possible to reduce the toxicity and side effects of pan-CDK inhibitors. Thus, as a combination therapy approach, pan-CDK inhibitors regain great potential in clinical application. In this review, we introduced the CDK family members and discussed their major functions in cell cycle controlling. Then, we summarized the research progress regarding CDK inhibitors, especially those other than CDK4/6 inhibitors. We reviewed first-generation pan-CDKIs Flavopiridol and Roscovitine, and second-generation CDKIs Dinaciclib, P276-00, AT7519, TG02, Roniciclib, RGB-286638 by focusing on their developing stages, clinical trials and targeting cancers. The specific CDKIs, which targets to increase specificity and decrease the side effects, were also discussed. These CDKIs include CDK4/6, CDK7, CDK9, and CDK12/13 inhibitors. Finally, the efficacy and discrepancy of combination therapy with CDK inhibitors and PD1/PDL1 antibodies were analyzed, which might give insights into the development of promising strategy for cancer treatment.
Conformational Adaption May Explain the Slow Dissociation Kinetics of Roniciclib (BAY 1000394), a Type I CDK Inhibitor with Kinetic Selectivity for CDK2 and CDK9
ACS Chem Biol 2016 Jun 17;11(6):1710-9.PMID:27090615DOI:10.1021/acschembio.6b00074.
Roniciclib (BAY 1000394) is a type I pan-CDK (cyclin-dependent kinase) inhibitor which has revealed potent efficacy in xenograft cancer models. Here, we show that roniciclib displays prolonged residence times on CDK2 and CDK9, whereas residence times on other CDKs are transient, thus giving rise to a kinetic selectivity of roniciclib. Surprisingly, variation of the substituent at the 5-position of the pyrimidine scaffold results in changes of up to 3 orders of magnitude of the drug-target residence time. CDK2 X-ray cocrystal structures have revealed a DFG-loop adaption for the 5-(trifluoromethyl) substituent, while for hydrogen and bromo substituents the DFG loop remains in its characteristic type I inhibitor position. In tumor cells, the prolonged residence times of roniciclib on CDK2 and CDK9 are reflected in a sustained inhibitory effect on retinoblastoma protein (RB) phosphorylation, indicating that the target residence time on CDK2 may contribute to sustained target engagement and antitumor efficacy.
BAY 1000394, a novel cyclin-dependent kinase inhibitor, with potent antitumor activity in mono- and in combination treatment upon oral application
Mol Cancer Ther 2012 Oct;11(10):2265-73.PMID:22821149DOI:10.1158/1535-7163.MCT-12-0286.
Deregulated activity of cyclin-dependent kinases (CDK) results in loss of cell-cycle checkpoint function and increased expression of antiapoptotic proteins, which has been directly linked to the molecular pathology of cancer. BAY 1000394 inhibits the activity of cell-cycle CDKs CDK1, CDK2, CDK3, CDK4, and of transcriptional CDKs CDK7 and CDK9 with IC(50) values in the range between 5 and 25 nmol/L. Cell proliferation was inhibited at low nanomolar concentration in a broad spectrum of human cancer cell lines. In cell-based assays, the inhibition of phosphorylation of the CDK substrates retinoblastoma protein, nucleophosmin, and RNA polymerase II was shown. Cell-cycle profiles were consistent with inhibition of CDK 1, 2, and 4 as shown in cell-cycle block and release experiments. The physicochemical and pharmacokinetic properties of BAY 1000394 facilitate rapid absorption and moderate oral bioavailability. The compound potently inhibits growth of various human tumor xenografts on athymic mice including models of chemotherapy resistance upon oral dosing. Furthermore, BAY 1000394 shows more than additive efficacy when combined with cisplatin and etoposide. These results suggest that BAY 1000394 is a potent pan-CDK inhibitor and a novel oral cytotoxic agent currently in phase I clinical trials.
Sulfoximines: a neglected opportunity in medicinal chemistry
Angew Chem Int Ed Engl 2013 Sep 2;52(36):9399-408.PMID:23934828DOI:10.1002/anie.201302209.
Innovation has frequently been described as the key to drug discovery. However, in the daily routine, medicinal chemists often tend to stick to the functional groups and structural elements they know and love. Blockbuster cancer drug Velcade (bortezomib), for example, was rejected by more than 50 companies, supposedly because of its unusual boronic acid function (as often repeated: "only a moron would put boron in a drug!"). Similarly, in the discovery process of the pan-CDK inhibitor BAY 1000394, the unconventional proposal to introduce a sulfoximine group into the lead series also led to sneers and raised eyebrows, since sulfoximines have seldom been used in medicinal chemistry. However, it was the introduction of the sulfoximine group that finally allowed the fundamental issues of the project to be overcome, culminating in the identification of the clinical sulfoximine pan-CDK inhibitor BAY 1000394. This Minireview provides an overview of a widely neglected opportunity in medicinal chemistry--the sulfoximine group.
Activity of Roniciclib in medullary thyroid cancer
Oncotarget 2018 Jun 15;9(46):28030-28041.PMID:29963260DOI:10.18632/oncotarget.25555.
Altered cyclin-dependent kinase activity is observed in many human malignancies. Cyclin-dependent kinases that promote cell cycle progression may be promising targets in the treatment of cancer. The therapeutic effects of Roniciclib, a cyclin-dependent kinase inhibitor for medullary thyroid cancer were investigated in the present study. Roniciclib inhibited medullary thyroid cancer cell proliferation in a dose-dependent manner. Roniciclib induced caspase-3 activity and contributed to apoptosis. Cell cycle progression was arrested in the G2 phase. In vivo, Roniciclib treatment retarded the growth of tumors of medullary thyroid cancer xenografts. In addition, Roniciclib in combination with sorafenib was more effective than either single treatment in a xenograft model. No morbidity was observed in animals treated with single Roniciclib therapy and combination treatment of Roniciclib and sorafenib. These data provide a rationale for clinical assessment of using Roniciclib in the treatment of patients with medullary thyroid cancer.