CFI-402257
目录号 : GC18491
CFI-402257是Mps1的选择性抑制剂，CFI-402227抑制Mps1，IC50值为1。
Cas No.:1610759-22-2
Sample solution is provided at 25 µL, 10mM.
Quality Control & SDS
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- Purity: >99.00%
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- SDS (Safety Data Sheet)
- Datasheet
| Kinase experiment [1]: | |
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Preparation Method |
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 |
1-400nM CFI-402257 for 4h |
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Applications |
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. |
| Cell experiment [2]: | |
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Cell lines |
MHCC97L cells |
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Preparation Method |
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 |
1/2.5uM Stattic for 24 or 48 h |
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Applications |
Micronucleus formation in human HCC cells treated with CFI-402257, Treatment with CMI-402257 increased DNA damage. |
| Animal experiment [3]: | |
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Animal models |
BALB/cAnN - nu mice |
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Preparation Method |
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 |
6 mg/kg/day CFI-402257 for 19 d |
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Applications |
TTK inhibition by CFI-402257 shrank HCC tumors and reduced lung metastasis. |
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References: [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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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].
References:
[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]。
| Cas No. | 1610759-22-2 | SDF | |
| 化学名 | N-cyclopropyl-4-[7-[[(cis-3-hydroxy-3-methylcyclobutyl)methyl]amino]-5-(3-pyridinyloxy)pyrazolo[1,5-a]pyrimidin-3-yl]-2-methyl-benzamide | ||
| Canonical SMILES | CC1=C(C(NC2CC2)=O)C=CC(C3=C4N=C(OC5=CN=CC=C5)C=C(NC[C@@H]6C[C@@](O)(C)C6)N4N=C3)=C1 | ||
| 分子式 | C28H30N6O3 | 分子量 | 498.6 |
| 溶解度 | DMSO : ≥ 125 mg/mL (233.63 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 | 2.0056 mL | 10.0281 mL | 20.0562 mL |
| 5 mM | 0.4011 mL | 2.0056 mL | 4.0112 mL |
| 10 mM | 0.2006 mL | 1.0028 mL | 2.0056 mL |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
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2.
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3. 以上所有助溶剂都可在 GlpBio 网站选购。
CFI-402257, a TTK inhibitor, effectively suppresses hepatocellular carcinoma
Proc Natl Acad Sci U S A2022 Aug 9;119(32):e2119514119.PMID: 35914158DOI: 10.1073/pnas.2119514119
Deregulation of cell cycle is a typical feature of cancer cells. Normal cells rely on the strictly coordinated spindle assembly checkpoint (SAC) to maintain the genome integrity and survive. However, cancer cells could bypass this checkpoint mechanism. In this study, we showed the clinical relevance of threonine tyrosine kinase (TTK) protein kinase, a central regulator of the SAC, in hepatocellular carcinoma (HCC) and its potential as therapeutic target. Here, we reported that a newly developed, orally active small molecule inhibitor targeting TTK (CFI-402257) effectively suppressed HCC growth and induced highly aneuploid HCC cells, DNA damage, and micronuclei formation. We identified that CFI-402257 also induced cytosolic DNA, senescence-like response, and activated DDX41-STING cytosolic DNA sensing pathway to produce senescence-associated secretory phenotypes (SASPs) in HCC cells. These SASPs subsequently led to recruitment of different subsets of immune cells (natural killer cells, CD4+ T cells, and CD8+ T cells) for tumor clearance. Our mass cytometry data illustrated the dynamic changes in the tumor-infiltrating immune populations after treatment with CFI-402257. Further, CFI-402257 improved survival in HCC-bearing mice treated with anti-PD-1, suggesting the possibility of combination treatment with immune checkpoint inhibitors in HCC patients. In summary, our study characterized CFI-402257 as a potential therapeutic for HCC, both used as a single agent and in combination therapy.
Functional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer
Proc Natl Acad Sci U S A2017 Mar 21;114(12):3127-3132.PMID: 28270606DOI: 10.1073/pnas.1700234114
Loss of cell-cycle control is a hallmark of human cancer. Cell-cycle checkpoints are essential for maintaining genome integrity and balanced growth and division. They are specifically deregulated in cancer cells and contain regulators that represent potential therapeutic targets. Monopolar spindle 1 (Mps1; also known as TTK protein kinase) is a core component of the spindle assembly checkpoint (SAC), a genome-surveillance mechanism that is important for cell survival, and has emerged as a candidate target for anticancer therapy. Here, we report the cellular and antitumor effects of CFI-402257, a potent (Mps1 Ki = 0.09 ¡À 0.02 nM; cellular Mps1 EC50 = 6.5 ¡À 0.5 nM), highly selective, and orally active small-molecule inhibitor of Mps1 that was identified through a drug-discovery program. Human cancer cells treated with CFI-402257 exhibit effects consistent with Mps1 kinase inhibition, specifically SAC inactivation, leading to chromosome missegregation, aneuploidy, and ultimately cell death. Oral administration of CFI-402257 in monotherapy or in combination with an anti-programmed cell death 1 (PD-1) antibody in mouse models of human cancer results in inhibition of tumor growth at doses that are well-tolerated. Our findings provide a rationale for the clinical evaluation of CFI-402257 in patients with solid tumors.
Tyrosine Threonine Kinase Inhibition Eliminates Lung Cancers by Augmenting Apoptosis and Polyploidy
Mol Cancer Ther2019 Oct;18(10):1775-1786.PMID: 31358662DOI: 10.1158/1535-7163.MCT-18-0864
The spindle assembly checkpoint maintains genomic integrity. A key component is tyrosine threonine kinase (TTK, also known as Mps1). TTK antagonism is hypothesized to cause genomic instability and cell death. Interrogating The Cancer Genome Atlas revealed high TTK expression in lung adenocarcinomas and squamous cell cancers versus the normal lung (P < 0.001). This correlated with an unfavorable prognosis in examined lung adenocarcinoma cases (P = 0.007). TTK expression profiles in lung tumors were independently assessed by RNA in situ hybridization. CFI-402257 is a highly selective TTK inhibitor. Its potent antineoplastic effects are reported here against a panel of well-characterized murine and human lung cancer cell lines. Significant antitumorigenic activity followed independent treatments of athymic mice bearing human lung cancer xenografts (6.5 mg/kg, P < 0.05; 8.5 mg/kg, P < 0.01) and immunocompetent mice with syngeneic lung cancers (P < 0.001). CFI-402257 antineoplastic mechanisms were explored. CFI-402257 triggered aneuploidy and apoptotic death of lung cancer cells without changing centrosome number. Reverse phase protein arrays (RPPA) of vehicle versus CFI-402257-treated lung cancers were examined using more than 300 critical growth-regulatory proteins. RPPA bioinformatic analyses discovered CFI-402257 enhanced MAPK signaling, implicating MAPK antagonism in augmenting TTK inhibitory effects. This was independently confirmed using genetic and pharmacologic repression of MAPK that promoted CFI-402257 anticancer actions. TTK antagonism exerted marked antineoplastic effects against lung cancers and MAPK inhibition cooperated. Future work should determine whether CFI-402257 treatment alone or with a MAPK inhibitor is active in the lung cancer clinic.
Discovery of Pyrazolo[1,5-a]pyrimidine TTK Inhibitors: CFI-402257 is a Potent, Selective, Bioavailable Anticancer Agent
ACS Med Chem Lett2016 May 6;7(7):671-5.PMID: 27437075DOI: 10.1021/acsmedchemlett.5b00485
This work describes a scaffold hopping exercise that begins with known imidazo[1,2-a]pyrazines, briefly explores pyrazolo[1,5-a][1,3,5]triazines, and ultimately yields pyrazolo[1,5-a]pyrimidines as a novel class of potent TTK inhibitors. An X-ray structure of a representative compound is consistent with 1(1)/2 type inhibition and provides structural insight to aid subsequent optimization of in vitro activity and physicochemical and pharmacokinetic properties. Incorporation of polar moieties in the hydrophobic and solvent accessible regions modulates physicochemical properties while maintaining potency. Compounds with enhanced oral exposure were identified for xenograft studies. The work culminates in the identification of a potent (TTK K i = 0.1 nM), highly selective, orally bioavailable anticancer agent (CFI-402257) for IND enabling studies.
Disruption of the anaphase-promoting complex confers resistance to TTK inhibitors in triple-negative breast cancer
Proc Natl Acad Sci U S A2018 Feb 13;115(7):E1570-E1577.PMID: 29378962DOI: 10.1073/pnas.1719577115
TTK protein kinase (TTK), also known as Monopolar spindle 1 (MPS1), is a key regulator of the spindle assembly checkpoint (SAC), which functions to maintain genomic integrity. TTK has emerged as a promising therapeutic target in human cancers, including triple-negative breast cancer (TNBC). Several TTK inhibitors (TTKis) are being evaluated in clinical trials, and an understanding of the mechanisms mediating TTKi sensitivity and resistance could inform the successful development of this class of agents. We 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. We used genome-wide CRISPR/Cas9 screens in multiple TNBC cell lines to identify mechanisms of resistance to CFI-402257. Our functional genomic screens identified members of the anaphase-promoting complex/cyclosome (APC/C) complex, which promotes mitotic progression following inactivation of the SAC. Several screen candidates were validated to confer resistance to CFI-402257 and other TTKis using CRISPR/Cas9 and siRNA methods. These findings extend the observation that impairment of the APC/C enables cells to tolerate genomic instability caused by SAC inactivation, and support the notion that a measure of APC/C function could predict the response to TTK inhibition. Indeed, an APC/C gene expression signature is significantly associated with CFI-402257 response in breast and lung adenocarcinoma cell line panels. This expression signature, along with somatic alterations in genes involved in mitotic progression, represent potential biomarkers that could be evaluated in ongoing clinical trials of CFI-402257 or other TTKis.