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BOS-172722

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Chemical Structure| 1578245-44-9 同义名 : -
CAS号 : 1578245-44-9
货号 : A1167620
分子式 : C24H30N8O
纯度 : 99%+
分子量 : 446.548
MDL号 : MFCD31692374
存储条件：

粉末 Keep in dark place,Inert atmosphere,Store in freezer, under -20°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

1M HCl: 50 mg/mL(111.97 mM)，配合低频超声，并调节pH至2
动物实验配方：
生物活性
描述 MPS1 (monopolar spindle 1, also known as TTK) is a dual specificity kinase that occupies a central role in mitosis. MPS1 is one of the main components of the spindle assembly checkpoint (SAC)1−4 and ensures cells do not progress from metaphase to anaphase until the kinetochores are properly attached to the microtubules and under the appropriate tension at the metaphase plate. Cancer cells heavily rely on MPS1 to cope with aneuploidy resulting from aberrant numbers of chromosomes[2]. High MPS1 was associated with poorer long term survival when all gliomas were analyzed combined in one group (Cox regression: t < 24 months, p = 0.009, Hazard ratio: 8.0, 95% CI: 1.7-38.4), with poorer survival solely in low-grade gliomas (LogRank: p = 0.02, Cox regression: p = 0.06, Hazard-Ratio: 8.0, 95% CI: 0.9-66.7), but not in GBM (LogRank: p > 0.05)[3]. BOS-172722 is an inhibitor of monopolar spindle 1 (MPS1) checkpoint with an IC50 of 2 nM and it also has potential for the treatment of various forms of breast cancer[4]. In in vivo pharmacodynamic experiments, BOS172722 potently inhibits the spindle assembly checkpoint induced by paclitaxel in human tumor xenograft models of TNBC, as measured by inhibition of the phosphorylation of histone H3 and the phosphorylation of the MPS1 substrate, KNL1. This mechanistic synergy results in significant in vivo efficacy, with robust tumor regressions observed for the combination of BOS172722 and paclitaxel versus either agent alone in long-term efficacy studies in multiple human tumor xenograft TNBC models, including a patient-derived xenograft and a systemic metastasis model[5].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.24mL

0.45mL

0.22mL

11.20mL

2.24mL

1.12mL

22.39mL

4.48mL

2.24mL
参考文献

[1]Woodward HL, Innocenti P, Cheung KJ, Hayes A, Roberts J, Henley AT, Faisal A, Mak GW, Box G, Westwood IM, Cronin N, Carter M, Valenti M, De Haven Brandon A, O'Fee L, Saville H, Schmitt J, Burke R, Broccatelli F, van Montfort RLM, Raynaud FI, Eccles SA, Linardopoulos S, Blagg J, Hoelder S. Introduction of a Methyl Group Curbs Metabolism of Pyrido[3,4- d]pyrimidine Monopolar Spindle 1 (MPS1) Inhibitors and Enables the Discovery of the Phase 1 Clinical Candidate N2-(2-Ethoxy-4-(4-methyl-4 H-1,2,4-triazol-3-yl)phenyl)-6-methyl- N8-neopentylpyrido[3,4- d]pyrimidine-2,8-diamine (BOS172722). J Med Chem. 2018 Sep 27;61(18):8226-8240. doi: 10.1021/acs.jmedchem.8b00690. Epub 2018 Sep 10. PMID: 30199249; PMCID: PMC6166229.

[2]Lauze E.;et al. Yeast spindle pole body duplication gene MPS1 encodes an essential dual specificity protein kinase. EMBO J. 1995, 14, 1655–1663

[3] Almuth F Kessler,et al. Monopolar Spindle 1 Kinase (MPS1/TTK) mRNA Expression is Associated with Earlier Development of Clinical Symptoms, Tumor Aggressiveness and Survival of Glioma Patients. Biomedicines. 2020 Jul 3;8(7):192.

[4]ARYL SULFONOHYDRAZIDES. WO 2014037750 A1.

[5]Simon J Anderhub,et al. High Proliferation Rate and a Compromised Spindle Assembly Checkpoint Confers Sensitivity to the MPS1 Inhibitor BOS172722 in Triple-Negative Breast Cancers. Mol Cancer Ther. 2019 Oct;18(10):1696-1707.