Simurosertib (TAK-931)
(Synonyms: TAK-931) 目录号 : GC32930
An inhibitor of Cdc7 kinase
Cas No.:1330782-76-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Simurosertib is an inhibitor of cell division cycle 7 (Cdc7) kinase (IC50 = 0.26 nM).1 It is selective for Cdc7 over cyclin-dependent kinase 2 (Cdk2) and Rho-associated kinase 1 (ROCK1; IC50s = 6,300 and 430 nM, respectively). It inhibits phosphorylation of DNA replication licensing factor MCM2 in HeLa cells (IC50 = 17 nM) and reduces proliferation of COLO 205 cells (EC50 = 81 nM). Simurosertib induces replication stress, halts the cell cycle at the G2/S phase, and inhibits the growth of a wide variety of cancer cells (GI50s = 30.2->10,000 nM).2 It reduces intratumor levels of phosphorylated MCM2 in COLO 205 and SW948 mouse xenograft models when administered at a dose of 80 mg/kg and reduces tumor growth in the same models when administered at doses of 40 or 60 mg/kg twice per day.
1.Kurasawa, O., Miyazaki, T., Homma, M., et al.Discovery of a novel, highly potent, and selective thieno[3,2- d]pyrimidinone-based cdc7 inhibitor with a quinuclidine moiety (tak-931) as an orally active investigational antitumor agentJ. Med. Chem.63(3)1084-1104(2020) 2.Iwai, K., Nambu, T., Dairiki, R., et al.Molecular mechanism and potential target indication of TAK-931, a novel CDC7-selective inhibitorSci. Adv.5(5)eaav3660(2019)
| Cas No. | 1330782-76-7 | SDF | |
| 别名 | TAK-931 | ||
| Canonical SMILES | O=C1C2=C(C=C(C3=CNN=C3C)S2)NC([C@H]4N(CC5)CCC5C4)=N1 | ||
| 分子式 | C17H19N5OS | 分子量 | 341.43 |
| 溶解度 | DMSO : 75 mg/mL (219.66 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 | 2.9289 mL | 14.6443 mL | 29.2886 mL |
| 5 mM | 0.5858 mL | 2.9289 mL | 5.8577 mL |
| 10 mM | 0.2929 mL | 1.4644 mL | 2.9289 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。
Molecular mechanism and potential target indication of TAK-931, a novel CDC7-selective inhibitor
Sci Adv 2019 May 22;5(5):eaav3660.PMID:31131319DOI:10.1126/sciadv.aav3660.
Replication stress (RS) is a cancer hallmark; chemotherapeutic drugs targeting RS are widely used as treatments for various cancers. To develop next-generation RS-inducing anticancer drugs, cell division cycle 7 (CDC7) has recently attracted attention as a target. We have developed an oral CDC7-selective inhibitor, TAK-931, as a candidate clinical anticancer drug. TAK-931 induced S phase delay and RS. TAK-931-induced RS caused mitotic aberrations through centrosome dysregulation and chromosome missegregation, resulting in irreversible antiproliferative effects in cancer cells. TAK-931 exhibited significant antiproliferative activity in preclinical animal models. Furthermore, in indication-seeking studies using large-scale cell panel data, TAK-931 exhibited higher antiproliferative activities in RAS-mutant versus RAS-wild-type cells; this finding was confirmed in pancreatic patient-derived xenografts. Comparison analysis of cell panel data also demonstrated a unique efficacy spectrum for TAK-931 compared with currently used chemotherapeutic drugs. Our findings help to elucidate the molecular mechanisms for TAK-931 and identify potential target indications.
Population Pharmacokinetics of TAK-931, a Cell Division Cycle 7 Kinase Inhibitor, in Patients With Advanced Solid Tumors
J Clin Pharmacol 2022 Mar;62(3):422-433.PMID:34564871DOI:10.1002/jcph.1974.
A population pharmacokinetic (PK) analysis was conducted to characterize sources of interpatient variability on the PK of TAK-931, a cell division cycle 7 kinase inhibitor, in adult patients with advanced solid tumors using data from 198 patients who received oral TAK-931 over the range of 30 to 150 mg once daily in multiple dosing schedules in 2 phase 1 and 1 phase 2 clinical studies. A 2-compartment model with 2 transit compartments describing the absorption and first-order linear elimination adequately described the PK of TAK-931. The apparent oral clearance (CL/F) of TAK-931 was estimated to be 38 L/h, and the terminal half-life was estimated to be approximately 6 hours. Creatinine clearance (CrCL) was identified as a covariate on CL/F, and body weight as a covariate on CL/F, apparent central volume of distribution, and apparent intercompartmental clearance. Simulations using the final model indicated that the effect of CrCL (≥35 mL/min) or body weight (29.8-127 kg) on TAK-931 systemic exposures was not considered clinically meaningful, suggesting that no dose adjustments were necessary to account for body weight or renal function (CrCL ≥35 mL/min). Sex, age (36-88 years), race, and mild hepatic impairment had no impact on the CL/F of TAK-931. Taken together, the population PK analysis supports the same starting dose of TAK-931 in Asian and Western cancer patients in a global setting.
Assessment of Effects of Investigational TAK-931, an Oral Cell Division Cycle 7 Kinase Inhibitor on the QTc Intervals in Patients With Advanced Solid Tumors
Clin Pharmacol Drug Dev 2022 Jun;11(6):770-779.PMID:35187855DOI:10.1002/cpdd.1075.
TAK-931, a novel, selective, small-molecule inhibitor of cell division cycle 7 has been investigated in multiple clinical trials in patients with advanced solid tumors. An integrated analysis using data from 2 clinical studies assessed effects of TAK-931 on electrocardiogram QT intervals and heart rate (HR). Pharmacokinetic samples and matched triplicate electrocardiogram data were collected in 48 patients with cancer receiving oral administration of TAK-931 50 or 80 mg once daily. The relationships between TAK-931 plasma concentrations and the HR-corrected QT interval via Fridericia (QTcF) or population (QTcP) and HR were analyzed using linear mixed-effects models with fixed effects for day and time. At the geometric mean maximum TAK-931 plasma concentrations after administration of 50 mg, an HR change of 3.40 beats per minute (90%CI, 1.86-4.80) was predicted. Change in QTcF of -3.41 milliseconds (90%CI, -5.77 to -1.17) and QTcP of -2.02 milliseconds (90%CI, -4.15 to 0.0679) were estimated, indicating there was no effect of TAK-931 on the QT intervals at a recommended phase 2 dose of 50 mg once daily for 14 days in a 21-day cycle.
A phase 1 open-label study to assess the relative bioavailability of TAK-931 tablets in reference to powder-in-capsule in patients with advanced solid tumors
Invest New Drugs 2023 Feb;41(1):53-59.PMID:36409435DOI:10.1007/s10637-022-01318-3.
In this phase 1 open-label study, we assessed the relative bioavailability of a prototype tablet formulation of TAK-931, a cell division cycle 7 kinase inhibitor, in reference to the current powder-in-capsule (PIC) formulation in patients with advanced solid tumors for whom no effective standard treatment was available. Adult patients were randomized 1:1 in a crossover fashion to receive one dose of TAK-931 80 mg PIC on Day 1 and one dose of TAK-931 80 mg tablet on Day 3 (or the reverse sequence), followed by TAK-931 50 mg PIC once daily (QD) for 12 days starting from Day 5, before a 7-day rest period (Cycle 0). From Cycle 1, all patients received 50 mg PIC QD on Days 1-14 followed by a 7-day rest period. Twenty patients were enrolled. Median Tmax was achieved approximately 2 h post-dose of TAK-931 80 mg for both tablet and PIC. Geometric mean Cmax, AUC exposures, and T1/2z of TAK-931 were similar for both formulations. Geometric mean Cmax, AUClast, and AUCinf ratios were 0.936 (90% confidence interval [CI]: 0.808-1.084), 1.004 (90% CI: 0.899-1.120), and 1.007 (90% CI: 0.903-1.123), respectively, for TAK-931 tablet in reference to PIC. Discontinuation of TAK-931 due to treatment-emergent adverse events (TEAEs) occurred in 1 patient. Four (20%) patients experienced a serious TEAE; none were considered related to TAK-931. Pharmacokinetics and systemic exposure profiles were similar following administration of both formulations, supporting the transition from PIC to tablet in the clinical development of TAK-931. (Trial registration number ClinicalTrials.gov NCT03708211. Registration date October 12, 2018).
Discovery of a Novel, Highly Potent, and Selective Thieno[3,2- d]pyrimidinone-Based Cdc7 Inhibitor with a Quinuclidine Moiety (TAK-931) as an Orally Active Investigational Antitumor Agent
J Med Chem 2020 Feb 13;63(3):1084-1104.PMID:31895562DOI:10.1021/acs.jmedchem.9b01427.
In our pursuit of developing a novel, potent, and selective cell division cycle 7 (Cdc7) inhibitor, we optimized the previously reported thieno[3,2-d]pyrimidinone analogue I showing time-dependent Cdc7 kinase inhibition and slow dissociation kinetics. These medicinal chemistry efforts led to the identification of compound 3d, which exhibited potent cellular activity, excellent kinase selectivity, and antitumor efficacy in a COLO205 xenograft mouse model. However, the issue of formaldehyde adduct formation emerged during a detailed study of 3d, which was deemed an obstacle to further development. A structure-based approach to circumvent the adduct formation culminated in the discovery of compound 11b (TAK-931) possessing a quinuclidine moiety as a preclinical candidate. In this paper, the design, synthesis, and biological evaluation of this series of compounds will be presented.