1. Protein Tyrosine Kinase/RTK
  2. Trk Receptor

LOXO-195 

Cat. No.: HY-101977 Purity: 98.89%
Handling Instructions

LOXO-195 is a next-generation TRK kinase inhibitor (TKI), with IC50s of 0.6 nM, <2.5 nM for TRKA and TRKC respectively.

For research use only. We do not sell to patients.

LOXO-195 Chemical Structure

LOXO-195 Chemical Structure

CAS No. : 2097002-61-2

Size Price Stock Quantity
10 mM * 1 mL in DMSO USD 715 In-stock
Estimated Time of Arrival: December 31
5 mg USD 650 In-stock
Estimated Time of Arrival: December 31
10 mg USD 990 In-stock
Estimated Time of Arrival: December 31
25 mg USD 1990 In-stock
Estimated Time of Arrival: December 31
50 mg USD 2750 In-stock
Estimated Time of Arrival: December 31
100 mg   Get quote  
200 mg   Get quote  

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Customer Review

  • Biological Activity

  • Protocol

  • Technical Information

  • Purity & Documentation

  • References

Description

LOXO-195 is a next-generation TRK kinase inhibitor (TKI), with IC50s of 0.6 nM, <2.5 nM for TRKA and TRKC respectively.

IC50 & Target[1]

TrkA

0.6 nM (IC50)

TrkC

<2.5 nM (IC50)

In Vitro

Both larotrectinib and LOXO-195 agents demonstrate strong binding to the wild-type TRKA, TRKB and TRKC kinase domains. Both drugs have potent (IC50<1 nM) inhibitory activity in kinase enzyme assays. Importantly, 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 LOXO-195 concentration of 1 μM, which is ~1667-fold higher than its IC50 for TRKA (0.6 nM). LOXO-195 is more than 1000-fold selective for 98% of non-TRK kinases tested. LOXO-195 demonstrates potent inhibition of cell proliferation in TRK fusion-containing KM12, CUTO-3, and MO-91 cell lines (IC50≤5 nM). In contrast, LOXO-195 treatment with concentrations up to 10 μM has no inhibitory effect on the growth of the 84 cell lines that does not contain a TRK fusion [1].

In Vivo

Stably transfected NIH-3T3 ΔTRKA and ΔTRKA-G595R cells are implanted subcutaneously into the flanks of nude mice. Both larotrectinib and LOXO-195 are effective at reducing phosphorylated TRKA in tumors driven by ΔTRKA. In contrast, only LOXO-195 strongly suppresses phospho-TRKA in ΔTRKA-G595R cells in a dose-dependent manner. 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. LOXO-195 displays high selectivity for the TRK proteins[1]

Solvent & Solubility
In Vitro: 

DMSO : 62.5 mg/mL (164.29 mM; Need ultrasonic)

Preparing
Stock Solutions
Concentration Solvent Mass 1 mg 5 mg 10 mg
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
*Please refer to the solubility information to select the appropriate solvent.
In Vivo:
  • 1.

    Add each solvent one by one:  10% DMSO    90% corn oil

    Solubility: ≥ 2.08 mg/mL (5.47 mM); Clear solution

  • 2.

    Add each solvent one by one:  10% DMSO    40% PEG300    5% Tween-80    45% saline

    Solubility: ≥ 2.08 mg/mL (5.47 mM); Clear solution

  • 3.

    Add each solvent one by one:  10% DMSO    90% (20% SBE-β-CD in saline)

    Solubility: ≥ 2.08 mg/mL (5.47 mM); Clear solution

References
Cell Assay
[1]

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., LOXO-195), each prepared as a 10-point, 1:3 dilution series with final concentrations ranging from 51 pM-1 μM and a constant DMSO concentration of 0.25%. 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. ELISA plates are analyzed by reading optical density. IC50 values are calculated[1].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[1]

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, 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, 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].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

References
Molecular Weight

380.42

Formula

C₂₀H₂₁FN₆O

CAS No.

2097002-61-2

SMILES

FC1=CN=C(CC[[email protected]](N2)C)C([[email protected]](CCC3)([H])N3C(C=CN4N=C5)=NC4=C5C2=O)=C1

Storage
Powder -20°C 3 years
  4°C 2 years
In solvent -80°C 6 months
  -20°C 1 month
Shipping

Room temperature in continental US; may vary elsewhere

Purity: 98.89%

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Product Name:
LOXO-195
Cat. No.:
HY-101977
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LOXO-195

Cat. No.: HY-101977