Pexidartinib (PLX3397)
(Synonyms: 培西达替尼,PLX-3397) 目录号 : GC12222
Pexidartinib(PLX3397) 是一种口服小分子酪氨酸激酶抑制剂，对集落刺激因子 1(CSF1) 受体 (IC50=20nM)、KIT 原癌基因受体酪氨酸激酶 (KIT)(IC50 = 10nM) 和类 FMS 酪氨酸激酶 3Pexidartinib 在体外是一种比伊马替尼更强的 KIT 抑制剂。
Cas No.:1029044-16-3
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| Cell experiment [1]: | |
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Cell lines |
LM8(RCB1450)、NFSa(RCB0282)、KUM5(RCB2322)、LAG(RCB2758) |
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Reaction Conditions |
a 10mmol/L stock of pexidartinib was formulated in dimethyl sulfoxide (DMSO) |
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Applications |
In vitro administration of pexidartinib suppressed pERK1/2 stimulation by CSF1 or TCM. CSF1R blockade in the in vitro TAM model resulted in reduced viability and chemotaxis of macrophages and polarization from M2-like to a more M1-like phenotype |
| Animal experiment [2]: | |
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Animal models |
Two-month-old 5XFAD mice |
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Preparation Method |
Treated two-month-old 5XFAD mice with pexidartinib, for a period of 3 months, resulting in a significant ablation of microglia. Directly after this treatment, analyse the amount of intraneuronal amyloid and neuritic plaques and performed behavioral studies including Y-maze, fear conditioning and elevated plus maze |
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Dosage form |
290mg/kg formulated in standard chow，3 month |
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Applications |
Early long-term treatment with the CSF1R inhibitor, pexidartinib significantly reduced intraneuronal amyloid, neuritic plaque formation, a reduced amount of toxic prefibrillar oligomers and improved cognitive function in particular associative learning in the contextual fear conditioning of 5XFAD mice. |
| Clinical trial [3]: | |
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human subjects |
Eligible patients were 18 years old or older and have a histologically confirmed TGCT that was both unresectable and symptomatic |
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Preparation Method |
The pooled analysis encompassed 3 groups of pexidartinib-treated patients with TGCT: 1) patients from a phase 1 extension study, 2) patients from ENLIVEN who were randomized to pexidartinib at 1000mg/d for 2 weeks and then 800mg/d, and 3) crossover patients from ENLIVEN receiving pexidartinib at 800mg/d. |
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Applications |
One hundred thirty patients with TGCT received pexidartinib (median treatment duration, 19 months; range, 1 to 76+ months); 54 (42%) remained on treatment at the end of the analysis (26 months after initial data cut of March 2017). The RECIST overall response rate (ORR) was 60%; the TVS ORR was 65%. The median times to response were 3.4 (RECIST) and 2.8 months (TVS), with 48 of the responding patients (62%) achieving a RECIST partial response by 6 months and with 72 (92%) doing so by 18 months. The median DOR was reached for TVS (46.8 months). Reported TEAEs were mostly low-grade, with hair color changes being most frequent (75%). Most liver abnormalities (92%) were aminotransferase elevations; 4 patients (3%) experienced mixed/cholestatic hepatotoxicity (all within the first 2 months of treatment), which was reversible in all cases (recovery spanned 1-7 months). |
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References: [1].Fujiwara T, Yakoub MA, Chandler A, et al. CSF1/CSF1R Signaling Inhibitor Pexidartinib (PLX3397) Reprograms Tumor-Associated Macrophages and Stimulates T-cell Infiltration in the Sarcoma Microenvironment. Mol Cancer Ther. 2021;20(8):1388-1399. [2].Sosna J, Philipp S, Albay R 3rd, et al. Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer's disease. Mol Neurodegener. 2018;13(1):11. Published 2018 Mar 1. [3].Gelderblom H, Wagner AJ, Tap WD, et al. Long-term outcomes of pexidartinib in tenosynovial giant cell tumors. Cancer. 2021;127(6):884-893. |
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Pexidartinib(PLX3397) is an orally administered small molecule tyrosine kinase inhibitor with potent selective activity against the colony-stimulating factor 1(CSF1) receptor(IC50=20nM), KIT proto-oncogene receptor tyrosine kinase(KIT)(IC50 =10nM) and FMS-like tyrosine kinase 3[1,2]
Pexidartinib was a stronger KIT inhibitor than imatinib in vitro. Compared pexidartinib and imatinib in vitro against 2 human GIST cell lines that harbor an imatinib-sensitive, activating KIT exon 11 mutation. Indeed, pexidartinib decreased viability in both cell lines with two-fold greater potency than imatinib, with an IC50 of 8-18 nM versus 42 nM(p<0.05). At concentrations similar to the IC50 of each drug, i.e., 10 and 40 nM, PLX3397 also decreased phospho-KIT relative to total KIT more effectively than imatinib in vitro[3]
Pexidartinib is effective in reducing adipose tissue macrophage levels of chow and high fat diet mice without affecting total myeloid cell levels[4]. A research found pexidartinib was well-tolerated in non-human primates(NHPs), with no Grade 3 or Grade 4 toxicities. Pexidartinib has limited CSF penetrance in NHPs following oral administration of a single dose[5]
Pexidartinib received its first approval on 2 August 2019 in the USA for the treatment of adult patients with symptomatic TGCT associated with severe morbidity or functional limitations and not amenable to improvement with surgery[2]
References:
[1].Fujiwara T, Yakoub MA, Chandler A, et al. CSF1/CSF1R Signaling Inhibitor Pexidartinib (PLX3397) Reprograms Tumor-Associated Macrophages and Stimulates T-cell Infiltration in the Sarcoma Microenvironment. Mol Cancer Ther. 2021;20(8):1388-1399.
[2].Lamb YN. Pexidartinib: First Approval [published correction appears in Drugs. 2020 Mar;80(4):447]. Drugs. 2019;79(16):1805-1812.
[3].Liu Y, Given KS, Dickson EL, et al. Concentration-dependent effects of CSF1R inhibitors on oligodendrocyte progenitor cells ex vivo and in vivo. Exp Neurol. 2019;318:32-41.
[4].Merry TL, Brooks AES, Masson SW, et al. The CSF1 receptor inhibitor pexidartinib (PLX3397) reduces tissue macrophage levels without affecting glucose homeostasis in mice. Int J Obes (Lond). 2020;44(1):245-253.
[5].Shankarappa PS, Peer CJ, Odabas A, et al. Cerebrospinal fluid penetration of the colony-stimulating factor-1 receptor (CSF-1R) inhibitor, pexidartinib. Cancer Chemother Pharmacol. 2020;85(5):1003-1007.
Pexidartinib(PLX3397) 是一种口服小分子酪氨酸激酶抑制剂,对集落刺激因子 1(CSF1) 受体 (IC50=20nM)、KIT 原癌基因受体酪氨酸激酶 (KIT)(IC50 = 10nM) 和类 FMS 酪氨酸激酶 3[1,2]
Pexidartinib 在体外是一种比伊马替尼更强的 KIT 抑制剂。将 pexidartinib 和伊马替尼在体外与 2 个人类 GIST 细胞系进行比较,这些细胞系具有伊马替尼敏感的激活 KIT 外显子 11 突变。事实上,pexidartinib 降低了两种细胞系的活力,效力是伊马替尼的两倍,IC50 分别为 8-18 nM 和 42 nM(p&<0.05)。在与每种药物的 IC50 相似的浓度下,即 10 和 40 nM,PLX3397 在体外也比伊马替尼更有效地降低磷酸化 KIT 相对于总 KIT[3]
Pexidartinib 可有效降低食物和高脂肪饮食小鼠的脂肪组织巨噬细胞水平,而不影响总骨髓细胞水平[4]。一项研究发现,pexidartinib 在非人类灵长类动物 (NHP) 中具有良好的耐受性,没有 3 级或 4 级毒性。 Pexidartinib 在 NHPs 中口服单剂量后 CSF 外显率有限[5]
Pexidartinib 于 2019 年 8 月 2 日在美国首次获得批准,用于治疗伴有严重发病率或功能受限且无法通过手术改善的症状性 TGCT 成年患者[2]/ p>
| Cas No. | 1029044-16-3 | SDF | |
| 别名 | 培西达替尼,PLX-3397 | ||
| 化学名 | 5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-amine | ||
| Canonical SMILES | ClC(C=N1)=CC2=C1NC=C2CC3=CN=C(NCC4=CN=C(C(F)(F)F)C=C4)C=C3 | ||
| 分子式 | C20H15ClF3N5 | 分子量 | 417.81 |
| 溶解度 | ≥ 20.9mg/mL in DMSO | 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 | 2.3934 mL | 11.9672 mL | 23.9343 mL |
| 5 mM | 0.4787 mL | 2.3934 mL | 4.7869 mL |
| 10 mM | 0.2393 mL | 1.1967 mL | 2.3934 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 | ||||||||||
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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。
CSF1/CSF1R Signaling Inhibitor Pexidartinib (PLX3397) Reprograms Tumor-Associated Macrophages and Stimulates T-cell Infiltration in the Sarcoma Microenvironment
Mol Cancer Ther2021 Aug;20(8):1388-1399.PMID: 34088832DOI: 10.1158/1535-7163.MCT-20-0591
Colony-stimulating factor 1 (CSF1) is a primary regulator of the survival, proliferation, and differentiation of monocyte/macrophage that sustains the protumorigenic functions of tumor-associated macrophages (TAMs). Considering current advances in understanding the role of the inflammatory tumor microenvironment, targeting the components of the sarcoma microenvironment, such as TAMs, is a viable strategy. Here, we investigated the effect of PLX3397 (pexidartinib) as a potent inhibitor of the CSF1 receptor (CSF1R). PLX3397 was recently approved by the Food and Drug Administration (FDA) to treat tenosynovial giant cell tumor and reprogram TAMs whose infiltration correlates with unfavorable prognosis of sarcomas. First, we confirmed by cytokine arrays of tumor-conditioned media (TCM) that cytokines including CSF1 are secreted from LM8 osteosarcoma cells and NFSa fibrosarcoma cells. The TCM, like CSF1, stimulated ERK1/2 phosphorylation in bone marrow-derived macrophages (BMDMs), polarized BMDMs toward an M2 (TAM-like) phenotype, and strikingly promoted BMDM chemotaxis. In vitro administration of PLX3397 suppressed pERK1/2 stimulation by CSF1 or TCM, and reduced M2 polarization, survival, and chemotaxis in BMDMs. Systemic administration of PLX3397 to the osteosarcoma orthotopic xenograft model significantly suppressed the primary tumor growth and lung metastasis, and thus improved metastasis-free survival. PLX3397 treatment concurrently depleted TAMs and FOXP3+ regulatory T cells and, surprisingly, enhanced infiltration of CD8+ T cells into the microenvironments of both primary and metastatic osteosarcoma sites. Our preclinical results show that PLX3397 has strong macrophage- and T-cell-modulating effects that may translate into cancer immunotherapy for bone and soft-tissue sarcomas.
Pexidartinib
Review2019 Aug 10;394(10197):478-487.PMID: 32352705DOI: 10.1016/S0140-6736(19)30764-0
No information is available on the clinical use of pexidartinib during breastfeeding. Because pexidartinib is over 99% bound to plasma proteins, the amount in milk is likely to be low. However, the manufacturer recommends that breastfeeding be discontinued during pexidartinib therapy and for 1 week after the last dose.
Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial
Lancet2019 Aug 10;394(10197):478-487.PMID: 31229240DOI: 10.1016/S0140-6736(19)30764-0
Background: Tenosynovial giant cell tumour (TGCT), a rare, locally aggressive neoplasm, overexpresses colony-stimulating factor 1 (CSF1). Surgery is standard with no approved systemic therapy. We aimed to evaluate pexidartinib, a CSF1 receptor inhibitor, in patients with TGCT to provide them with a viable systemic treatment option, especially in cases that are not amenable to surgical resection.
Methods: This phase 3 randomised trial had two parts. Part one was a double-blind study in which patients with symptomatic, advanced TGCT for whom surgery was not recommended were randomly assigned via an integrated web response system (1:1) to the pexidartinib or placebo group. Individuals in the pexidartinib group received a loading dose of 1000 mg pexidartinib per day orally (400 mg morning; 600 mg evening) for the first 2 weeks, followed by 800 mg per day (400 mg twice a day) for 22 weeks. Part two was an open-label study of pexidartinib for all patients. The primary endpoint, assessed in all intention-to-treat patients, was overall response at week 25, and was centrally reviewed by RECIST, version 1.1. Safety was analysed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02371369.
Findings: Between May 11, 2015, and Sept 30, 2016, of 174 patients assessed for eligibility, 120 patients were randomly assigned to, and received, pexidartinib (n=61) or placebo (n=59). There were 11 dropouts in the placebo group and nine in the pexidartinib group. Emergence of mixed or cholestatic hepatotoxicity caused the data monitoring committee to stop enrolment six patients short of target. The proportion of patients who achieved overall response was higher for pexidartinib than placebo at week 25 by RECIST (24 [39%] of 61 vs none of 59; absolute difference 39% [95% CI 27-53]; p<0·0001). Serious adverse events occurred in eight (13%) of 61 patients in the pexidartinib group and one (2%) of 59 patients in the placebo group. Hair colour changes (67%), fatigue (54%), aspartate aminotransferase increase (39%), nausea (38%), alanine aminotransferase increase (28%), and dysgeusia (25%) were the most frequent pexidartinib-associated adverse events. Three patients given pexidartinib had aminotransferase elevations three or more times the upper limit of normal with total bilirubin and alkaline phosphatase two or more times the upper limit of normal indicative of mixed or cholestatic hepatotoxicity, one lasting 7 months and confirmed by biopsy.
Interpretation: Pexidartinib is the first systemic therapy to show a robust tumour response in TGCT with improved patient symptoms and functional outcomes; mixed or cholestatic hepatotoxicity is an identified risk. Pexidartinib could be considered as a potential treatment for TGCT associated with severe morbidity or functional limitations in cases not amenable to improvement with surgery.
Funding: Daiichi Sankyo.
Pexidartinib
Review2019 Nov;79(16):1805-1812.PMID: 31869194DOI: 10.1007/s40265-019-01210-0
Pexidartinib is an orally available small molecule multi-kinase inhibitor that is used as an antineoplastic agent in the treatment of tenosynovial giant cell tumors. Pexidartinib is associated with a high rates of serum aminotransferase and alkaline phosphatase elevations during therapy and has been implicated in several cases of clinically apparent liver injury marked by progressive intrahepatic bile duct injury, some of which resulted in liver transplantation or were fatal.
Pexidartinib: First Approval
Drugs2019 Nov;79(16):1805-1812.PMID: 31602563DOI: 10.1007/s40265-019-01210-0
Pexidartinib (TURALIO™) is an orally administered small molecule tyrosine kinase inhibitor with selective activity against the colony-stimulating factor 1 (CSF1) receptor, KIT proto-oncogene receptor tyrosine kinase (KIT) and FMS-like tyrosine kinase 3 harboring an internal tandem duplication mutation (FLT3-ITD). In August 2019, the US FDA approved pexidartinib capsules for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. This approval was based on positive results from the phase III ENLIVEN trial. Pexidartinib is being investigated in various malignancies as monotherapy or combination therapy. This article summarizes the milestones in the development of pexidartinib leading to its first approval for TGCT.