LOXO-101 (Larotrectinib) sulfate
(Synonyms: (3S)-N-[5-[(2R)-2-(2,5-二氟苯基)-1-吡咯烷基]吡唑并[1,5-A]嘧啶-3-基]-3-羟基-1-吡咯烷甲酰胺硫酸盐,LOXO-101 sulfate; ARRY-470 sulfate) 目录号 : GC15282
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LOXO-101 (Larotrectinib) sulfate是一种口服可用的ATP竞争性泛TRK抑制剂，对TRKA和TRKC的IC50值分别为0.9nM和2.8nM。
Cas No.:1223405-08-0
Sample solution is provided at 25 µL, 10mM.
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LOXO-101 (Larotrectinib) sulfate is orally available, ATP-competitive pan-TRK inhibitor, with IC50 values of 0.9nM and 2.8nM for TRKA and TRKC, respectively [1]. LOXO-101 sulfate preferentially blocks the ATP-binding site of TRKA, TRKB, and TRKC, thereby inhibiting the TRK catalytic activity, the autophosphorylation, and the activation of downstream pathways [2]. LOXO-101 sulfate has been widely used in preclinical models to inhibit tumor growth[3].
In vitro, LOXO-101 sulfate treatment for 72 hours significantly inhibited the proliferation of CUTO-3.29 cells, KM12 cells and MO-91 cells, with IC50 values of 59nM, 3.5nM and 1nM, respectively[4]. Treatment with 300nM LOXO-101 sulfate for 24 hours significantly upregulated the expression of the epithelial marker E-cadherin in HCT116 cells, decreased the expression of mesenchymal markers (including vimentin and MMP2), and inhibited cell migration[5]. Treatment of T98G cells with 1μM LOXO-101 sulfate for 24 hours induced apoptosis, disrupted mitochondrial membrane potential and upregulated the activities of caspase 3, 8 and 9[6].
In vivo, LOXO-101 sulfate treatment via oral administration at a dose of 200mg/kg/day for 6 weeks significantly reduced the levels of leukemic infiltration in the bone marrow and spleen of the patient-derived xenograft (PDX) mouse model of ETV6-NTRK3 [7]. Oral administration of LOXO-101 sulfate (50mg/kg) three times a week for 5 weeks can significantly inhibit the growth of tumors in a 143B/NGF (overexpressed NGF) cell-xenograft mouse model, without affecting the weight of the mice[8].
References:
[1] Drilon A, Nagasubramanian R, Blake J F, et al. A next-generation TRK kinase inhibitor overcomes acquired resistance to prior TRK kinase inhibition in patients with TRK fusion–positive solid tumors[J]. Cancer discovery, 2017, 7(9): 963-972.
[2] Berger S, Martens U M, Bochum S. Larotrectinib (LOXO-101)[J]. Small Molecules in Oncology, 2018: 141-151.
[3] Hong D S, Brose M S, Doebele R C, et al. Abstract PR13: Clinical safety and activity from a phase 1 study of LOXO-101, a selective TRKA/B/C inhibitor, in solid-tumor patients with NTRK gene fusions[J]. Molecular Cancer Therapeutics, 2015, 14(12_Supplement_2): PR13-PR13.
[4] Doebele R C, Davis L E, Vaishnavi A, et al. An oncogenic NTRK fusion in a patient with soft-tissue sarcoma with response to the tropomyosin-related kinase inhibitor LOXO-101[J]. Cancer discovery, 2015, 5(10): 1049-1057.
[5] Kong W, Zhu H, Zheng S, et al. Larotrectinib induces autophagic cell death through AMPK/mTOR signalling in colon cancer[J]. Journal of cellular and molecular medicine, 2022, 26(21): 5539-5550.
[6] Zając A, Sumorek-Wiadro J, Maciejczyk A, et al. The engagement of Ras/Raf/MEK/ERK and PLCγ1/PKC pathways regulated by TrkB receptor in resistance of glioma cells to elimination upon apoptosis induction[J]. Neuropharmacology, 2025, 262: 110204.
[7] Roberts K G, Bridges O, Janke L J, et al. Genetic Modeling and Therapeutic Targeting of ETV6-NTRK3 with Loxo-101in Acute Lymphoblastic Leukemia[J]. Blood, 2016, 128(22): 278.
[8] Hou C H, Chen W L, Lin C Y. Targeting nerve growth factor-mediated osteosarcoma metastasis: mechanistic insights and therapeutic opportunities using larotrectinib[J]. Cell Death & Disease, 2024, 15(5): 381.
LOXO-101 (Larotrectinib) sulfate是一种口服可用的ATP竞争性泛TRK抑制剂，对TRKA和TRKC的IC50值分别为0.9nM和2.8nM[1]。LOXO-101 sulfate优先阻断TRKA、TRKB和TRKC的ATP结合位点，从而抑制TRK催化活性、自磷酸化及下游通路的激活[2]。LOXO-101 sulfate已被广泛用于临床前模型以抑制肿瘤生长[3]。
在体外，LOXO-101 sulfate处理72小时显著抑制了CUTO-3.29细胞、KM12细胞和MO-91细胞的增殖，IC50值分别为59nM、3.5nM和1nM[4]。使用300nM的LOXO-101 sulfate处理24小时，显著上调了HCT116细胞中上皮标志物E-cadherin的表达，降低了间充质标志物（包括vimentin和MMP2）的表达，并抑制了细胞迁移[5]。使用1µM的LOXO-101 sulfate处理T98G细胞24小时，诱导了细胞凋亡，破坏了线粒体膜电位，并上调了caspase 3、8和9的活性[6]。
在体内，每日口服给予200mg/kg/day的LOXO-101 sulfate，持续6周，显著降低了ETV6-NTRK3患者来源异种移植（PDX）小鼠模型中骨髓和脾脏的白血病浸润水平[7]。每周三次口服给予LOXO-101 sulfate（50mg/kg），持续5周，可显著抑制143B/NGF（过表达NGF）细胞异种移植小鼠模型中的肿瘤生长，且不影响小鼠的体重[8]。
| Cell experiment [1]: | |
Cell lines | KM12 cells |
Preparation Method | KM12 cells were maintained in DMEM medium supplemented with, 100units/ml penicillin plus 100µg/ml streptomycin, and heat-inactivated fetal calf serums to a final concentration of 10% in humidified atmosphere with 5% CO2 at 37°C. Cells were seeded in 96-well plates at a density of 1000 cells per well. After 24h, cells were incubated in the presence of different concentrations of LOXO-101 sulfate (0, 1, 10, 100, 1000, and 10000nM), or the vehicle alone (DMSO) for 72h. Cell proliferation was measured. |
Reaction Conditions | 0, 1, 10, 100, 1000, and 10000nM; 72h |
Applications | LOXO-101 sulfate treatment inhibited the cell viability of KM12 cells in a dose-dependent manner. |
| Animal experiment [2]: | |
Animal models | Male BALB/c nude mice |
Preparation Method | Male BALB/c nude mice (4 weeks old, weighing 24±2g) were housed in an SPF animal facility with 12/12h light/dark cycle (25±1℃, humidity 60±10%), and fed with laboratory regular diet and sterilized water ad libitum. Under 1.5–2.5% isoflurane anesthesia, 5×106 143B/NGF cells were implanted into the right tibia of each mouse using a solution comprising 50% serum-free DMEM and 50% matrigel (total volume of 100μl). The mice in the 143B/NGF+LOXO-101 sulfate group were administered LOXO-101 sulfate (50mg/kg) orally three times a week for five weeks. Body weights and tumor volumes were assessed regularly. |
Dosage form | 50mg/kg; three times a week for five weeks; p.o. |
Applications | LOXO-101 sulfate treatment significantly inhibited 143B/NGF tumor growth without affecting the body weight of the mice. |
References: | |
| Cas No. | 1223405-08-0 | SDF | |
| 别名 | (3S)-N-[5-[(2R)-2-(2,5-二氟苯基)-1-吡咯烷基]吡唑并[1,5-A]嘧啶-3-基]-3-羟基-1-吡咯烷甲酰胺硫酸盐,LOXO-101 sulfate; ARRY-470 sulfate | ||
| 化学名 | (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide sulfate | ||
| Canonical SMILES | O=S(O)(O)=O.O=C(N1C[C@@H](O)CC1)NC2=C3N=C(N4[C@@H](C5=CC(F)=CC=C5F)CCC4)C=CN3N=C2 | ||
| 分子式 | C21H24F2N6O6S | 分子量 | 526.51 |
| 溶解度 | DMSO : 100mg/mL | 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 | 1.8993 mL | 9.4965 mL | 18.993 mL |
| 5 mM | 379.9 μL | 1.8993 mL | 3.7986 mL |
| 10 mM | 189.9 μL | 949.6 μL | 1.8993 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。
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- Purity: >99.50% Appearance: A solid
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