| CAS |
No.2097002-61-2 |
| 英文名称 |
Selitrectinib |
| 别名 |
LOXO-195 |
| 分子式 |
C20H21FN6O |
| 分子量 |
380.43 |
| 溶解性 |
Soluble in DMSO ≥4mg/mL(Need ultrasonic) |
| 纯度 |
≥98% |
| 外观(性状) |
White to yellow Solid |
| 储存条件 |
Powder:2-8℃，2 years;Insolvent(母液):-20℃，6 months;-80℃，1 year |
| MDL |
MFCD31620755 |
| SMILES |
C[C@@H]1CCC2=C(C=C(C=N2)F)[C@H]3CCCN3C4=NC5=C(C=NN5C=C4)C(=O)N1 |
| InChIKey |
OEBIHOVSAMBXIB-SJKOYZFVSA-N |
| InChI |
InChI=1S/C20H21FN6O/c1-12-4-5-16-14(9-13(21)10-22-16)17-3-2-7-26(17)18-6-8-27-19(25-18)15(11-23-27)20(28)24-12/h6，8-12，17H，2-5，7H2，1H3，(H，24，28)/t12-，17-/m1/s1 |
| PubChem CID |
129103609 |
| 靶点 |
Trk Receptor |
| 通路 |
Protein Tyrosine Kinase/RTK;Neuronal Signaling |
| 背景说明 |
Selitrectinib是一种具有口服活性、高度有效的、选择性TRK激酶抑制剂。 |
| 生物活性 |
Selitrectinib (LOXO-195) is a next-generation TRK kinase inhibitor， with IC50s of 0.6 nM and TRKA and TRKC， respectively.[1] |
| In Vitro |
Selitrectinib (LOXO-195) demonstrates strong binding to the wild-type TRKA， TRKB and TRKC kinase domains. Selitrectinib (LOXO-195) has potent (IC50enzyme assays. Importantly， Selitrectinib (LOXO-195) achieves low nanomolar inhibitory activity against TRKA G595R， TRKC G623R， and TRKA G667C， with IC50s ranging from 2.0-9.8 nM. 228 individual kinases in vitro are profiled at a Selitrectinib (LOXO-195) concentration of 1 μM， which is ~1667-fold higher than its IC50 for TRKA (0.6 nM). Selitrectinib (LOXO-195) is more than 1000-fold selective for 98% of non-TRK kinases tested. Selitrectinib (LOXO-195) demonstrates potent inhibition of cell proliferation in TRK fusion-containing KM12， CUTO-3， and MO-91 cell lines (IC50≤5 nM)[1]. |
| In Vivo |
Stably transfected NIH-3T3 ΔTRKA and ΔTRKA-G595R cells are implanted subcutaneously into the flanks of nude mice. Both larotrectinib and Selitrectinib (LOXO-195) are effective at reducing phosphorylated TRKA in tumors driven by ΔTRKA. In contrast， only Selitrectinib (LOXO-195) strongly suppresses phospho-TRKA in ΔTRKA-G595R cells in a dose-dependent manner. Selitrectinib (LOXO-195) also causes inhibition of tumor growth relative to vehicle at all doses in four TRKA-dependent tumor models (ΔTRKA， ΔTRKA-G595R， ΔTRKAG667C， and TPM3-NTRK1 fusion-positive KM12 colorectal cancer cells. Larotrectinib inhibits KM12 and NIH 3T3-ΔTRKA tumors to a similar degree. Group mean body weight loss does not exceed 5% for any agent. Selitrectinib (LOXO-195) displays high selectivity for the TRK proteins[1] |
| 细胞实验 |
For assessment of cellular inhibition potency， cells are harvested per a standard protocol， counted and added to flat-bottom， collagen I-coated 96-well assay plates at 3×104 cells/well (wild-type cell line) or 5×104 cells/well (mutant cell lines) in 100 μL/well of DMEM growth medium containing 10% FBS. Plates are then incubated at room temperature for 30 minutes prior to an overnight incubation at 37°C with 5% CO2. Next， cells are treated for 1 hour at 37°C， 5% CO2 with TRK inhibitor compounds (e.g.， Selitrectinib (LOXO-195)). Control wells contain either 0.25% DMSO alone or 1 μM larotrectinib or LOXO-195. Following compound incubation， growth medium is discarded and cells are lysed by addition of 60 μL/well of ice-cold lysis buffer containing protease and phosphatase inhibitors[1]. |
| 动物实验 |
Mice[1]The ΔTRKA， ΔTRKA-G595R， and ΔTRKA -G667C NIH-3T3 tumor cell lines (~2-3x106 cells) and KM12 cells (5x106 cells) are injected subcutaneously into the right flank of female nu/nu NCr mice. Tumors are allowed to grow to ~100-200 mm3 or ~500 mm3， and animals are randomized by tumor size into dosing groups of 5 (KM12)， 7 (NIH 3T3 ΔTRKA variants) or 3-4 (for PK-PD) animals. Animals are dosed by oral gavage with vehicle， Selitrectinib (LOXO-195) in 1% carboxymethylcellulose/0.5% Tween-80 or larotrectinib in 100% Labrafac lipophile. All animals are obtained at 6-8 weeks of age， housed in groups of 5 and allowed a one-week acclimation period before cancer cell injection. Animals are dosed with vehicle twice daily， Selitrectinib (LOXO-195) at 30 mg/kg， 100 mg/kg and 300 mg/kg twice daily and larotrectinib at 60 mg/kg daily for 9-12 days. Body weight and tumor size are monitored after cell implantation and at regular intervals during dosing[1]. |
| 数据来源文献 |
[1]. Drilon A， et al. A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors. Cancer Discov. 2017 Sep;7(9):963-972. |
| 规格 |
1mg 5mg 10mg 25mg 50mg 100mg |
| 单位 |
瓶 |
中文
英语
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