APS03118 (compound 5) showed significantly better inhibitory activity against RET solvent front G810 mutations than Selpercatinib and Pralsetinib [1]. APS03118 demonstrated superior efficacy against ERT resistance mutations (such as solvent front and gatekeeper mutations) and exhibited potent antiproliferative activity comparable to Pralsetinib and Selpercatinib (IC50 = 10.08 nM) in naturally RET fusion-positive LC2/ad lung cancer cells [1]. APS03118 (0-3000 nM) can strongly inhibit RET autophosphorylation in Ba/F3 KIF5B-RET, Ba/F3 KIF5B-RET V804M, Ba/F3 KIF5B-RET G810R and Ba/F3 KIF5B-RET M918T cells, with IC50 values of 1.91, 1.18, 14.66 and 2.28 nM, respectively [1]. APS03118 (0-1000 nM, 1.5 h) can effectively inhibit the entire RET signaling pathway (including RET, Shc and ERK1/2) in TT-RET C634W cells at low nanomolar concentrations [1].

APS03118 (3, 10 and 30 mg/kg, interfacial, twice daily for 28 days) showed potent antitumor activity in both the KIF5B-RET and CCDC6-RET V804M PDX simulation models [1]. APS03118 (10 and 30 mg/kg, interfacial, twice daily for 90 days) blocked tumor growth in the intracranial CCDC6-RET and CCDC6-RET V804M CDX tumor models [1].

Western Blot Analysis[1]
Cell Types: TT-RET C634W cells
Tested Concentrations: 0, 1, 10, 100, and 1000 nM
Incubation Duration: 1.5 h
Experimental Results: Almost abolished the phosphorylation of RET, Shc and ERK1/2 at 10 nM, whereas Selpercatinib and Pralsetinib only partially inhibited it. Inhibited the phosphorylation of RET, Shc, and ERK1/2 at concentrations below 10 nM.

Animal/Disease Models: Female BALB/c nude mice (6-8 weeks) subcutaneously implanted with KIF5B-RET tumors[1]
Doses: 3, 10 and 30 mg/kg
Route of Administration: p.o., BID for 28 days
Experimental Results: Inhibited tumor growth in a dose-dependent manner, with TGI of 85, 107, and 109% at 3, 10, and 30 mg/kg, respectively. Significantly reduced tumor volumes on day 17 compared to the vehicle. Achieved complete tumor regression at 10 and 30 mg/kg at the study end point, matching the efficacy of Selpercatinib at its 10 mg/kg dose. Revealed no significant body weight changes.

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Animal/Disease Models: Female BALB/c nude mice (6-8 weeks) subcutaneously implanted with CCDC6-RET V804M tumors[1]
Doses: 3, 10 and 30 mg/kg
Route of Administration: p.o., BID for 28 days
Experimental Results: Achieved tumor growth inhibition of 88, 99, and 100%, at 3, 10, and 30 mg/kg, respectively. Reduced tumor volumes in all tested group. Reduced tumor size at 3 and 10 mg/kg, with efficacy comparable to Selpercatinib at its 10 mg/kg dose. Revealed no significant body weight changes.

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Animal/Disease Models: Female BALB/c nude mice (6-8 weeks) intracranially implanted with CCDC6-RET tumors into the brain[1]
Doses: 10 and 30 mg/kg
Route of Administration: p.o., BID for 90 days
Experimental Results: Significantly prolonged the survival time and demonstrated a 100% survival rate at a dose of 10 mg/kg. Induced complete regression of brain tumors at 10 and 30 mg/kg.

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Animal/Disease Models: Female BALB/c nude mice (6-8 weeks) subcutaneously injected with Ba/F3 KIF5B-RET G810R cells[1]
Doses: 10 and 30 mg/kg
Route of Administration: p.o., BID for 15 days
Experimental Results: Induced potent tumor growth inhibition with a TGI of 90% at 30 mg/kg, while Selpercatinib achieved only 48% TGI at the same dose. Exhibited greater efficacy than Selpercatinib in slowing the growth of Ba/F3 KIF5B-RET G810R allograft tumors at the same dose. Exhibited excellent tolerability at 10 and 30 mg/kg, with no significant body weight loss or apparent abnormalities in mice. Significantly reduced tumor volume compared to control on day 11.

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Animal/Disease Models: Female BALB/c nude mice (6-8 weeks) subcutaneously injected with Ba/F3 KIF5B-RET V804M cells[1]
Doses: 10 mg/kg
Route of Administration: p.o., BID for 14 days
Experimental Results: Achieved considerably higher TGI rates of 61% compared to Selpercatinib (10 mg/kg, p.o., BID; TGI = 48%). Was well-tolerated with no significant body weight loss in mice compared to the vehicle group during the treatment period.

[1]. https://pubmed.ncbi.nlm.nih.gov/40920215/

C27H28N8O2

496.56

2598870-24-5

Typically exists as solids at room temperature

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)