Selitrectinib-LOXO-195-DataSheet-生命科学试剂-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemESelitrectinibCat. No.: HY-101977CAS No.: 2097002-61-2Synonyms: LOXO-195分式: CHFNO分量: 380.42作靶点: Trk Receptor作通路: Neuronal Signaling; Protein Tyrosine Kinase/RTK储存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 mont

2、h溶解性数据体外实验 DMSO : 62.5 mg/mL (164.29 mM; Need ultrasonic)Mass Solvent1 mg 5 mg 10 mg Concentration制备储备液1 mM 2.6287 mL 13.1434 mL 26.2867 mL5 mM 0.5257 mL 2.6287 mL 5.2573 mL10 mM 0.2629 mL 1.3143 mL 2.6287 mL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，并请注意储备液的保存式和期限。体内实验请根据您的实验动物和给药式选择适当的溶解案，配制前请先配制澄清的储备液，再依次添加助溶剂

3、(为保证实验结果的可靠性，体内实验的作液，建议您现现配，当天使；澄清的储备液可以根据储存条件，适当保存；以下溶剂前的百分 指该溶剂在您配制终溶液中的体积占)：1. 请依序添加每种溶剂： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.08 mg/mL (5.47 mM); Clear solution2. 请依序添加每种溶剂： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.08 mg/mL (5.47 mM); Clear solution3. 请依序添加每种溶剂： 10% DM

4、SO 90% corn oil1/3 Master of Small Molecules 您边的抑制剂师www.MedChemESolubility: 2.08 mg/mL (5.47 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 Selitrectinib (LOXO-195)原肌凝蛋相关激酶 (TRK) 的个代抑制剂，其对 TRKA 和 TRKC 的 IC50 值分别为 0.6 nM 和 2.5 nM。IC50 & Target TrkA TrkC0.6 nM (IC50) 50)体外研究 Selitrectinib (LOXO-195) demons

5、trates strong binding to the wild-type TRKA, TRKB and TRKC kinasedomains. Selitrectinib (LOXO-195) has potent (IC5050s ranging from 2.0-9.8 nM. 228 individual kinases invitro are profiled at a Selitrectinib (LOXO-195) concentration of 1 M, which is 1667-fold higher than its IC50for TRKA (0.6 nM). Se

6、litrectinib (LOXO-195) is more than 1000-fold selective for 98% of non-TRK kinasestested. Selitrectinib (LOXO-195) demonstrates potent inhibition of cell proliferation in TRK fusion-containingKM12, CUTO-3, and MO-91 cell lines (IC505 nM) 1.体内研究 Stably transfected NIH-3T3 TRKA and TRKA-G595R cells ar

7、e implanted subcutaneously into the flanks ofnude mice. Both larotrectinib and Selitrectinib (LOXO-195) are effective at reducing phosphorylated TRKA intumors driven by TRKA. In contrast, only Selitrectinib (LOXO-195) strongly suppresses phospho-TRKA in TRKA-G595R cells in a dose-dependent manner. S

8、elitrectinib (LOXO-195) also causes inhibition of tumorgrowth relative to vehicle at all doses in four TRKA-dependent tumor models (TRKA, TRKA-G595R, TRKAG667C, and TPM3-NTRK1 fusion-positive KM12 colorectal cancer cells. Larotrectinib inhibits KM12and NIH 3T3-TRKA tumors to a similar degree. Group

9、mean body weight loss does not exceed 5% for anyagent. Selitrectinib (LOXO-195) displays high selectivity for the TRK proteins 1PROTOCOLCell Assay 1 For assessment of cellular inhibition potency, cells are harvested per a standard protocol, counted and addedto flat-bottom, collagen I-coated 96-well

10、assay plates at 3104 cells/well (wild-type cell line) or 5104cells/well (mutant cell lines) in 100 L/well of DMEM growth medium containing 10% FBS. Plates are thenincubated at room temperature for 30 minutes prior to an overnight incubation at 37C with 5% CO2. Next,cells are treated for 1 hour at 37

11、C, 5% CO2 with TRK inhibitor compounds (e.g., Selitrectinib (LOXO-195).Control wells contain either 0.25% DMSO alone or 1 M larotrectinib or LOXO-195. Following compoundincubation, growth medium is discarded and cells are lysed by addition of 60 L/well of ice-cold lysis buffercontaining protease and

12、 phosphatase inhibitors 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice 1Administration 1 The TRKA, TRKA-G595R, and TRKA -G667C NIH-3T3 tumor cell lines (2-3x106 cells) and KM12 cells(5x106 cells) are injected subcutaneously into the right

13、 flank of female nu/nu NCr mice. Tumors are allowedto grow to 100-200 mm3 or 500 mm3, and animals are randomized by tumor size into dosing groups of 52/3 Master of Small Molecules 您边的抑制剂师www.MedChemE(KM12), 7 (NIH 3T3 TRKA variants) or 3-4 (for PK-PD) animals. Animals are dosed by oral gavage withve

14、hicle, 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 dail

15、y, Selitrectinib(LOXO-195) at 30 mg/kg, 100 mg/kg and 300 mg/kg twice daily and larotrectinib at 60 mg/kg daily for 9-12days. Body weight and tumor size are monitored after cell implantation and at regular intervals during dosing1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.REFERENCES1. Drilon A, et al. A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients withTRK Fusion-Positive Solid Tumors. Ca