Background
CFI-402257 is a selective inhibitor of Mps1, CFI-402257 inhibited Mps1 with an IC50 value of 1.2 ± 0.4 nM, and was ATP competitive with a Ki value of 0.09 ± 0.02 nM, It has high specificity, selectivity and potency [2,7].
CFI-402257 induces senescence-like responses and SASP secretion in HCC[1]. CFI-402257 suppresses MM(Malignant mesothelioma) growth. Mps-1 is overexpressed in MM and that its expression correlates with poor patients' outcome. In vitro, CFI-402257-mediated inhibition of Mps-1 resulted in abrogation of the mitotic checkpoint, premature progression through mitosis, marked aneuploidy and mitotic catastrophe[3]. CFI-402257, significantly inhibited GBM cell proliferation and improved the growth-suppressive effect of TMZ[4]. When evaluated the cellular effects of the potent clinical TTKi CFI-402257 in TNBC models. CFI-402257 induced apoptosis and potentiated aneuploidy in TNBC lines by accelerating progression through mitosis and inducing mitotic segregation errors[6].
In BALB/cAnN - nu mice, TTK inhibition by CFI-402257 shrank HCC tumors and reduced lung metastasis[1]. Oral QD of CMI-402257 showed dose-dependent activity in mice with established tumors in xenografts of MDA-MB-231 human TNBC cells[2]. Developed a panel of CDK4/6i-resistant breast cancer cell lines and patient-derived organoids, TTK inhibitor CFI-402257 as a therapeutic strategy for a defined subset of ER+ breast cancer patients who develop resistance to CDK4/6i[6].
参考文献:
[1]: Chan CY, Chiu DK, et,al. CFI-402257, a TTK inhibitor, effectively suppresses hepatocellular carcinoma. Proc Natl Acad Sci U S A. 2022 Aug 9;119(32):e2119514119. doi: 10.1073/pnas.2119514119. Epub 2022 Aug 1. PMID: 35914158; PMCID: PMC9371652.
[2]: Mason JM, Wei X, et,al. Functional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer. Proc Natl Acad Sci U S A. 2017 Mar 21;114(12):3127-3132. doi: 10.1073/pnas.1700234114. Epub 2017 Mar 7. PMID: 28270606; PMCID: PMC5373378.
[3]: Szymiczek A, Carbone M, et,al. Inhibition of the spindle assembly checkpoint kinase Mps-1 as a novel therapeutic strategy in malignant mesothelioma. Oncogene. 2017 Nov 16;36(46):6501-6507. doi: 10.1038/onc.2017.266. Epub 2017 Jul 31. PMID: 28759042; PMCID: PMC5690838.
[4]: Yu J, Gao G, et,al.TTK Protein Kinase promotes temozolomide resistance through inducing autophagy in glioblastoma. BMC Cancer. 2022 Jul 18;22(1):786. doi: 10.1186/s12885-022-09899-1. PMID: 35850753; PMCID: PMC9290216.
[5]: Thu KL, Silvester J, et,al.Disruption of the anaphase-promoting complex confers resistance to TTK inhibitors in triple-negative breast cancer. Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):E1570-E1577. doi: 10.1073/pnas.1719577115. Epub 2018 Jan 29. PMID: 29378962; PMCID: PMC5816201.
[6]: Soria-Bretones I, Thu KL, et,al.The spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor-resistant ER+ breast cancer with mitotic aberrations. Sci Adv. 2022 Sep 9;8(36):eabq4293. doi: 10.1126/sciadv.abq4293. Epub 2022 Sep 7. PMID: 36070391; PMCID: PMC9451148.
[7]: Laufer R, Li SW, et,al. Discovery of 4-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamides as novel, highly potent and selective, orally bioavailable inhibitors of Tyrosine Threonine Kinase, TTK. Bioorg Med Chem Lett. 2016 Aug 1;26(15):3562-6. doi: 10.1016/j.bmcl.2016.06.021. Epub 2016 Jun 9. PMID: 27335255.
CFI-402257 是 Mps1 的选择性抑制剂，CFI-402257 抑制 Mps1 的 IC50 值为 1.2 ±； 0.4 nM，与 ATP 竞争，Ki 值为 0.09 ±； 0.02 nM，具有高特异性、选择性和效力 [2,7]。
CFI-402257 在 HCC 中诱导衰老样反应和 SASP 分泌[1]。 CFI-402257 抑制 MM（恶性间皮瘤）的生长。 Mps-1 在 MM 中过表达，其表达与贫困患者相关 '；结果。在体外，CFI-402257 介导的 Mps-1 抑制导致有丝分裂检查点的废除、有丝分裂过早进展、显着的非整倍体和有丝分裂灾难[3]。 CFI-402257，显着抑制 GBM 细胞增殖并改善 TMZ[4] 的生长抑制作用。当评估有效的临床 TTKi CFI-402257 在 TNBC 模型中的细胞效应时。 CFI-402257 通过加速有丝分裂进展和诱导有丝分裂分离错误，在 TNBC 细胞系中诱导细胞凋亡和增强非整倍体[6]。
在 BALB/cAnN - nu 小鼠中，CFI-402257 抑制 TTK 可缩小 HCC 肿瘤和减少肺转移[1]。 CMI-402257 的口服 QD 在 MDA-MB-231 人 TNBC 细胞异种移植物中已建立肿瘤的小鼠中表现出剂量依赖性活性[2]。开发了一组 CDK4/6i 抗性乳腺癌细胞系和患者来源的类器官，TTK 抑制剂 CFI-402257 作为对 CDK4/6i 产生抗性的特定 ER+ 乳腺癌患者亚群的治疗策略[6]。
Protocol
| Kinase experiment [1]: |
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Preparation Method
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HCT116 cells transfected with full-length human Mps1 were treated with nocodazole for 17 hours and pretreated with MG132 for 30 minutes, followed by treatment with CFI-402257 or DMSO for 4 hours to target phospho-MPS1 (T12/S15) and Mps1,The lysates were analyzed by Western blot analysis
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Reaction Conditions
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1-400nM CFI-402257 for 4h
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Applications
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CFI-402257 inhibited Mps1 with an IC50 value of 1.2 ± 0.4 nM, and was ATP competitive with a Ki value of 0.09 ± 0.02 nM.
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| Cell experiment [2]: |
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Cell lines
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MHCC97L cells
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Preparation Method
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MHCC97L cells were treated with different concentrations of CFI-402257 for 48 h and stained with DAPI for DNA staining.
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Reaction Conditions
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1/2.5uM Stattic for 24 or 48 h
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Applications
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Micronucleus formation in human HCC cells treated with CFI-402257, Treatment with CMI-402257 increased DNA damage.
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| Animal experiment [3]: |
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Animal models
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BALB/cAnN - nu mice
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Preparation Method
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BALB/cAnN-nu mice were orthotopically implanted with luciferase-labeled MHCC97L cells for 2 wk and were administered with vehicle control (Ctrl) or 6 mg/kg/day CFI-402257 for 19 d.
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Dosage form
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6 mg/kg/day CFI-402257 for 19 d
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Applications
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TTK inhibition by CFI-402257 shrank HCC tumors and reduced lung metastasis.
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参考文献:
[1]. Mason JM, Wei X, et,al. Functional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer. Proc Natl Acad Sci U S A. 2017 Mar 21;114(12):3127-3132. doi: 10.1073/pnas.1700234114. Epub 2017 Mar 7. PMID: 28270606; PMCID: PMC5373378.
[2]. Chan CY, Chiu DK, et,al. CFI-402257, a TTK inhibitor, effectively suppresses hepatocellular carcinoma. Proc Natl Acad Sci U S A. 2022 Aug 9;119(32):e2119514119. doi: 10.1073/pnas.2119514119. Epub 2022 Aug 1. PMID: 35914158; PMCID: PMC9371652.
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