2. Protein Tyrosine Kinase/RTK PI3K/Akt/mTOR Stem Cell/Wnt MAPK/ERK Pathway
  3. RET VEGFR PDGFR Akt ERK
  4. RET-IN-33

RET-IN-33 is a moderately selective inhibitor of RET mutants. RET-IN-33 potently inhibits G810 mutants, with IC50 values of 4.43 nM (G810R), 3.28 nM (G810C) and 0.51 nM (G810S), respectively. RET-IN-33 also inhibits other RET mutants: V804M (IC50 0.73 nM), V804L (IC50 0.36 nM), Y806H (IC50 0.74 nM) and M918T (IC50 0.55 nM). RET-IN-33 also inhibits other kinases, with an IC50 of 1.50 nM against VEGFR2 and 1.60 nM against PDGFRα. RET-IN-33 blocks the autophosphorylation of RET mutants and the downstream SHC/AKT/ERK signaling pathway. RET-IN-33 selectively inhibits the proliferation of RET-driven cell models without affecting non-RET-dependent or normal cells. RET-IN-33 exhibits dose-dependent antitumor efficacy in RET-driven xenograft models. RET-IN-33 can be used for the research of medullary thyroid carcinoma, papillary thyroid carcinoma and non-small cell lung cancer.

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

RET-IN-33

RET-IN-33 Chemical Structure

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RET-IN-33 Related Antibodies

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Description

RET-IN-33 is a moderately selective inhibitor of RET mutants. RET-IN-33 potently inhibits G810 mutants, with IC50 values of 4.43 nM (G810R), 3.28 nM (G810C) and 0.51 nM (G810S), respectively. RET-IN-33 also inhibits other RET mutants: V804M (IC50 0.73 nM), V804L (IC50 0.36 nM), Y806H (IC50 0.74 nM) and M918T (IC50 0.55 nM). RET-IN-33 also inhibits other kinases, with an IC50 of 1.50 nM against VEGFR2 and 1.60 nM against PDGFRα. RET-IN-33 blocks the autophosphorylation of RET mutants and the downstream SHC/AKT/ERK signaling pathway. RET-IN-33 selectively inhibits the proliferation of RET-driven cell models without affecting non-RET-dependent or normal cells. RET-IN-33 exhibits dose-dependent antitumor efficacy in RET-driven xenograft models. RET-IN-33 can be used for the research of medullary thyroid carcinoma, papillary thyroid carcinoma and non-small cell lung cancer[1].

IC50 & Target[1]

VEGFR2

1.50 nM (IC50)

PDGFRα

1.60 nM (IC50)

In Vitro

RET-IN-33 (Compound CN-3) potently inhibits wild-type RET and multiple clinically relevant RET kinase mutants, with IC50 values ranging from 0.36 nM to 40.2 nM across all tested RET subtypes[1].
RET-IN-33 (1.50-54.8 nM) potently inhibits PDGFRα and VEGFR2 with IC50 values of 1.60 nM and 1.50 nM, respectively, while exerts weak inhibitory activity against FGFR1 with an IC50 value of 54.8 nM[1].
RET-IN-33 (72 h) potently and selectively inhibits the proliferation of RET-dependent TT and LC-2/ad cells, with IC50 values of 2.48 nM and 17.05 nM, respectively[1].
RET-IN-33 (1-100 nM in TT cells, 10-1000 nM in LC-2/ad cells; 24 h) induces dose-dependent G0−G1 cell cycle arrest in TT and LC-2/ad cells, increasing the proportion of G0−G1 phase cells to 75.1% and 79.0% at the highest tested concentrations, respectively[1].

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

RET-IN-33 Related Antibodies

Cell Proliferation Assay[1]

Cell Line: RET-dependent human cancer cell lines (TT, LC-2/ad)
Concentration: A certain concentration
Incubation Time: 72 h
Result: Inhibited proliferation of TT cells with an IC50 of 2.48 nM.
Inhibited proliferation of LC-2/ad cells with an IC50 of 17.05 nM.
Outperformed pralsetinib in TT cells.

Cell Proliferation Assay[1]

Cell Line: Ba/F3 cells expressing RET fusions or resistance mutations (Ba/F3-CCDC6-RET, Ba/F3-CCDC6-RET-V804M, Ba/F3-CCDC6-RET-G810C, Ba/F3-CCDC6-RET-G810R, Ba/F3-KIF5B-RET, Ba/F3-KIF5B-RET-V804M, Ba/F3-KIF5B-RET-G810C, Ba/F3-KIF5B-RET-G810R)
Concentration: A certain concentration
Incubation Time: 72 h
Result: Inhibited proliferation of Ba/F3-CCDC6-RET cells with an IC50 of 6.1 nM.
Inhibited proliferation of Ba/F3-CCDC6-RET-V804M cells with an IC50 of 13.6 nM.
Inhibited proliferation of Ba/F3-CCDC6-RET-G810C cells with an IC50 of 15.3 nM.
Inhibited proliferation of Ba/F3-CCDC6-RET-G810R cells with an IC50 of 10.9 nM.
Inhibited proliferation of Ba/F3-KIF5B-RET cells with an IC50 of 24.1 nM.
Inhibited proliferation of Ba/F3-KIF5B-RET-V804M cells with an IC50 of 25.5 nM.
Inhibited proliferation of Ba/F3-KIF5B-RET-G810C cells with an IC50 of 91.9 nM.
Inhibited proliferation of Ba/F3-KIF5B-RET-G810R cells with an IC50 of 59.6 nM.
Retained far higher potency against G810 mutants compared to pralsetinib.

Cell Proliferation Assay[1]

Cell Line: non-RET-dependent human cancer and normal cell lines (A549, HepG2, HCT-116, KMS-28PE, OCI, MDA-MB-231, HeLa, A375, 293T, HUVEC)
Concentration: A certain concentration
Incubation Time: 72 h
Result: Showed minimal sensitivity in A549, HepG2, OCI, and A375 cells (IC50 > 10 μM).
Inhibited growth of HCT-116 cells with an IC50 of 3760.01 nM.
Inhibited growth of KMS-28PE cells with an IC50 of 5099.82 nM.
Inhibited growth of MDA-MB-231 cells with an IC50 of 3018.00 nM.
Inhibited growth of HeLa cells with an IC50 of 2701.01 nM.
Inhibited growth of 293T cells with an IC50 of 810.93 nM.
Inhibited growth of HUVEC cells with an IC50 of 5676.00 nM.

Cell Cycle Analysis[1]

Cell Line: RET-dependent human cancer cell lines (TT, LC-2/ad)
Concentration: 1-100 nM (TT cells); 10-1000 nM (LC-2/ad cells)
Incubation Time: 24 h
Result: Increased the proportion of G0−G1 phase TT cells to 54.1%, 64.1%, and 75.1% at 1, 10, and 100 nM, respectively (vs 53.5% in control).
Increased the proportion of G0−G1 phase LC-2/ad cells to 60.6%, 70.3%, and 79.0% at 10, 100, and 1000 nM, respectively.
Parmacokinetics
Species Dose Route Cmax AUC0-∞ CL T1/2 Bioavailability
Mice[1] 1 mg/kg i.v. 330 ng/mL 126 8115 mL/h/kg 0.690 h /
Mice[1] 10 mg/kg p.o. 50.7 ng/mL 72.9 / 0.835 h 5.8 %
In Vivo

RET-IN-33 (10-50 mg/kg; i.p.; once daily; 14 days) exhibits significant dose-dependent antitumor activity in the LC-2/ad xenograft model, reaching a maximum TGI of 160% at the 50 mg/kg dose, with good tolerance[1].
RET-IN-33 (10-25 mg/kg; i.p.; once daily; for 10 consecutive days) exerts dose-dependent antitumor activity against Ba/F3-CCDC6-RETG810R xenografts, achieving a TGI of 61.9% at the dose of 25 mg/kg, with good tolerance[1].

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

Animal Model: BALB/c nude (female, 6−8 weeks old, 18−20 g, subcutaneous xenograft of LC-2/ad cells)[1]
Dosage: 10 mg/kg; 25 mg/kg; 50 mg/kg
Administration: i.p.; daily; 14 days
Result: Induced dose-dependent tumor growth inhibition with tumor growth inhibition (TGI) values of 123%, 135%, and 160% at 10, 25, and 50 mg/kg, respectively.
Increased corresponding tumor inhibitory rates (IR) from 63.8% to 82.2%.
Caused no significant body-weight loss across all doses.
Animal Model: NOD-SCID (female, 6−8 weeks old, 18−20 g, subcutaneous xenograft of Ba/F3-CCDC6-RET-G810R cells)[1]
Dosage: 10 mg/kg; 25 mg/kg
Administration: i.p.; daily; 10 days
Result: Induced dose-dependent tumor growth inhibition with TGI values of 33.2% and 61.9% at 10 and 25 mg/kg, respectively.
Increased corresponding tumor IR were 22.6% and 52.5%.
Caused no significant body-weight loss across all doses.
Molecular Weight

553.58

Formula

C28H30F3N7O2
SMILES

O=C(NC1=CC=C(CN2CCN(C(C)C)CC2)C(C(F)(F)F)=C1)NC3=CC=C(C4=C5C(ON=C5N)=NC=C4)C=C3
Shipping

Room temperature in continental US; may vary elsewhere.
Storage

Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
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RET-IN-33 Related Classifications

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Help & FAQs
  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

RET-IN-33RETVEGFRPDGFRAktERKVascular endothelial growth factor receptorPlatelet-derived growth factor receptorPKBProtein kinase BExtracellular signal regulated kinasesSHCAKTPDGFRαpapillary thyroid carcinomanonsmall cell lung cancermedullary thyroid carcinomaVEGFR2FGFR1Inhibitorinhibitorinhibit

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