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Selitrectinib (LOXO-195) Sale

(Synonyms: LOXO-195) 目录号 : GC32808

A Trk kinase inhibitor

Selitrectinib (LOXO-195) Chemical Structure

Cas No.:2097002-61-2

规格 价格 库存 购买数量
10mM (in 1mL DMSO)
¥589.00
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5mg
¥704.00
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10mg
¥1,114.00
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25mg
¥2,228.00
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50mg
¥3,870.00
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100mg
¥6,450.00
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实验参考方法

Cell experiment:

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].

Animal experiment:

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].

References:

[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.

产品描述

LOXO-195 is an inhibitor of the receptor tyrosine kinases TrkA and TrkC (IC50s = 0.6 and <2.5 nM, respectively, in kinase assays).1 It also inhibits several Trk kinase mutants, including TrkAG595R, TrkAG667C, TrkCG623R, and TrkCG696A (IC50s = 2, 9.8, 2.3, and <2.5 nM, respectively). LOXO-195 binds to the kinase domain of TrkB with an IC50 value of 1.9 nM. It selectively inhibits proliferation of Trk fusion-positive K12, CUTO-3, and MO-91 cell lines (IC50s = ≤5 nM) over Trk fusion-negative cell lines when used at concentrations up to 10 μM. LOXO-195 (≥30 mg/kg) reduces tumor growth in TrkA-dependent KM12, as well as NIH 3T3 ΔTrkA, ΔTrkA + TrkAG595R, and ΔTrkA + TrkAG667C mouse xenograft models.

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 tumorsCancer Discov.7(9)963-972(2017)

Chemical Properties

Cas No. 2097002-61-2 SDF
别名 LOXO-195
Canonical SMILES FC1=CN=C(CC[C@H](N2)C)C([C@](CCC3)([H])N3C(C=CN4N=C5)=NC4=C5C2=O)=C1
分子式 C20H21FN6O 分子量 380.42
溶解度 DMSO : 62.5 mg/mL (164.29 mM) 储存条件 Store at -20°C
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1 mM 2.6287 mL 13.1434 mL 26.2867 mL
5 mM 0.5257 mL 2.6287 mL 5.2573 mL
10 mM 0.2629 mL 1.3143 mL 2.6287 mL
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Research Update

NTRK fusion-positive cancers and TRK inhibitor therapy

Nat Rev Clin Oncol 2018 Dec;15(12):731-747.PMID:30333516DOI:10.1038/s41571-018-0113-0.

NTRK gene fusions involving either NTRK1, NTRK2 or NTRK3 (encoding the neurotrophin receptors TRKA, TRKB and TRKC, respectively) are oncogenic drivers of various adult and paediatric tumour types. These fusions can be detected in the clinic using a variety of methods, including tumour DNA and RNA sequencing and plasma cell-free DNA profiling. The treatment of patients with NTRK fusion-positive cancers with a first-generation TRK inhibitor, such as larotrectinib or entrectinib, is associated with high response rates (>75%), regardless of tumour histology. First-generation TRK inhibitors are well tolerated by most patients, with toxicity profiles characterized by occasional off-tumour, on-target adverse events (attributable to TRK inhibition in non-malignant tissues). Despite durable disease control in many patients, advanced-stage NTRK fusion-positive cancers eventually become refractory to TRK inhibition; resistance can be mediated by the acquisition of NTRK kinase domain mutations. Fortunately, certain resistance mutations can be overcome by second-generation TRK inhibitors, including LOXO-195 and TPX-0005 that are being explored in clinical trials. In this Review, we discuss the biology of NTRK fusions, strategies to target these drivers in the treatment-naive and acquired-resistance disease settings, and the unique safety profile of TRK inhibitors.

TRK inhibitors in TRK fusion-positive cancers

Ann Oncol 2019 Nov 1;30(Suppl_8):viii23-viii30.PMID:31738426DOI:10.1093/annonc/mdz282.

TRK fusions are oncogenic drivers of various adult and paediatric cancers. The first-generation TRK inhibitors, larotrectinib and entrectinib, were granted landmark, tumour-agnostic regulatory approvals for the treatment of these cancers in 2018 and 2019, respectively. Brisk and durable responses are achieved with these drugs in patients, including those with locally advanced or metastatic disease. In addition, intracranial activity has been observed with both agents in TRK fusion-positive solid tumours with brain metastases and primary brain tumours. While resistance to first-generation TRK inhibition can eventually occur, next-generation agents such as Selitrectinib (BAY 2731954, LOXO-195) and repotrectinib were designed to address on-target resistance, which is mediated by emergent kinase domain mutations, such as those that result in substitutions at solvent front or gatekeeper residues. These next-generation drugs are currently available in the clinic and proof-of-concept responses have been reported. This underscores the utility of sequential TRK inhibitor use in select patients, a paradigm that parallels the use of targeted therapies in other oncogenic driver-positive cancers, such as ALK fusion-positive lung cancers. While TRK inhibitors have a favourable overall safety profile, select on-target adverse events, including weight gain, dizziness/ataxia and paraesthesias, are occasionally observed and should be monitored in the clinic. These side-effects are likely consequences of the inhibition of the TRK pathway that is involved in the development and maintenance of the nervous system.

NTRK fusions in lung cancer: From biology to therapy

Lung Cancer 2021 Nov;161:108-113.PMID:34563714DOI:10.1016/j.lungcan.2021.09.005.

Fusions involving TRK protein tyrosine kinases are oncogenic drivers in a variety of tumors in children and adults, with a prevalence of ∼0.2% in non-small cell lung cancer. Diagnosis can be challenging due to structural features such as NTRK intron length, but next-generation sequencing (NGS), including RNA-based NGS, increases detection. The first-generation TRK inhibitors, larotrectinib and entrectinib, have demonstrated clinically meaningful antitumor activity in TRK fusion-positive cancers in a tumor-agnostic fashion and should be considered first-line therapeutic options for TRK fusion-positive lung cancers. Furthermore, the first-generation TRK inhibitors are well tolerated. Care should be taken, however, to monitor on-target adverse events, such as dizziness, weight gain, paresthesias, and withdrawal pain. On-target and off-target mechanisms mediating TRK inhibitor resistance may occur. Next-generation TRK inhibitors, such as Selitrectinib, repotrectinib, and taletrectinib, are available on ongoing clinical trials and address on-target resistance. This review will focus on NTRK fusions and TRK-directed targeted therapy specifically in the context of lung cancer.

TRK inhibitor activity and resistance in TRK fusion-positive cancers in adults

Cancer Genet 2022 Jun;264-265:33-39.PMID:PMC9133157DOI:10.1016/j.cancergen.2022.03.002.

NTRK fusions drive oncogenesis in a variety of adult cancers. The approval of the first-generation TRK inhibitors, larotrectinib and entrectinib, for any cancer with an NTRK fusion represented a focal point in tumor-agnostic drug development. These agents achieve high response rates and durable disease control, and display intracranial activity. The use of these agents has resulted in a deeper understanding of the clinical consequences of TRK inhibition. These on-target side effects include dizziness, weight gain, and withdrawal pain. The study of TRK inhibitor resistance led to the development of next generation drugs, such as Selitrectinib, repotrectinib, taletrectinib, and other agents that maintain disease control against selected acquired kinase domain mutations. This review discusses the clinical efficacy of TRK inhibitors, their safety profiles, and resistance mechanisms with a focus on data in adult cancers.

TRK inhibitors in TRK fusion-positive cancers

Ann Oncol 2019 Nov;30 Suppl 8:viii23-viii30.PMID:32223935DOI:10.1093/annonc/mdz282.

TRK fusions are oncogenic drivers of various adult and paediatric cancers. The first-generation TRK inhibitors, larotrectinib and entrectinib, were granted landmark, tumour-agnostic regulatory approvals for the treatment of these cancers in 2018 and 2019, respectively. Brisk and durable responses are achieved with these drugs in patients, including those with locally advanced or metastatic disease. In addition, intracranial activity has been observed with both agents in TRK fusion-positive solid tumours with brain metastases and primary brain tumours. While resistance to first-generation TRK inhibition can eventually occur, next-generation agents such as Selitrectinib (BAY 2731954, LOXO-195) and repotrectinib were designed to address on-target resistance, which is mediated by emergent kinase domain mutations, such as those that result in substitutions at solvent front or gatekeeper residues. These next-generation drugs are currently available in the clinic and proof-of-concept responses have been reported. This underscores the utility of sequential TRK inhibitor use in select patients, a paradigm that parallels the use of targeted therapies in other oncogenic driver-positive cancers, such as ALK fusion-positive lung cancers. While TRK inhibitors have a favourable overall safety profile, select on-target adverse events, including weight gain, dizziness/ataxia and paraesthesias, are occasionally observed and should be monitored in the clinic. These side-effects are likely consequences of the inhibition of the TRK pathway that is involved in the development and maintenance of the nervous system.