2. MAPK/ERK Pathway Stem Cell/Wnt Protein Tyrosine Kinase/RTK
  3. ERK RET
  4. APS03118

APS03118 is an orally active, potent and selective rearranged during transfection (RET) inhibitor. APS03118 broadly inhibits RET fusions and mutations (including G810, V804, L730, and Y806 variants), with IC50 values predominantly below 1 nM (0.095 nM for WT; ranging from 0.00438 to 5.72 nM for mutants), and demonstrates marked superiority against RET G810 mutations. APS03118 inhibits the entire RET signaling pathway (including RET, Shc, and ERK1/2), with >20-fold selectivity over most off-target kinases (except FLT3 and YES). APS03118 induces complete tumor regression in KIF5B-RET and CCDC6-RET V804 M patient derived xenografts (PDXs) and significantly prolongs survival in an intracranial CCDC6-RET metastasis mice model. APS03118 can be used for selective RET inhibitor (SRI)-resistant, RET-driven cancer research.

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APS03118

APS03118 Chemical Structure

CAS No. : 2598870-24-5

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Description

APS03118 is an orally active, potent and selective rearranged during transfection (RET) inhibitor. APS03118 broadly inhibits RET fusions and mutations (including G810, V804, L730, and Y806 variants), with IC50 values predominantly below 1 nM (0.095 nM for WT; ranging from 0.00438 to 5.72 nM for mutants), and demonstrates marked superiority against RET G810 mutations. APS03118 inhibits the entire RET signaling pathway (including RET, Shc, and ERK1/2), with >20-fold selectivity over most off-target kinases (except FLT3 and YES). APS03118 induces complete tumor regression in KIF5B-RET and CCDC6-RET V804 M patient derived xenografts (PDXs) and significantly prolongs survival in an intracranial CCDC6-RET metastasis mice model. APS03118 can be used for selective RET inhibitor (SRI)-resistant, RET-driven cancer research[1].

In Vitro

APS03118 (compound 5) shows markedly superior activity against the solvent-front RET G810 mutation compared to Selpercatinib (HY-114370) and Pralsetinib (HY-112301)[1].
APS03118 exhibits superior efficacy against resistant RET mutations in engineered models (solvent-front and gatekeeper) and also demonstrates potent antiproliferative activity comparable to Pralsetinib and Selpercatinib in a native RET fusion-positive LC2/ad lung cancer cells (IC50 = 10.08 nM)[1].
APS03118 (0-3000 nM) inhibits 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[1].
APS03118 (0-1000 nM, 1.5 h) potently inhibits the entire RET signaling pathway (including RET, Shc, and ERK1/2) in TT-RET C634W cells at low nanomolar concentrations[1].

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

APS03118 Related Antibodies

Western Blot Analysis[1]

Cell Line: TT-RET C634W cells
Concentration: 0, 1, 10, 100, and 1000 nM
Incubation Time: 1.5 h
Result: 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.
In Vivo

APS03118 (3, 10 and 30 mg/kg, p.o., BID for 28 days) shows potent anti-tumor effects in KIF5B-RET and CCDC6-RET V804M PDX mice models[1].
APS03118 (10 and 30 mg/kg, p.o., BID for 90 days) eliminates intracranial tumors and prolongs survival in an intracranial CCDC6-RET mice metastasis model[1].
APS03118 (10 and 30 mg/kg, p.o., BID for 14 and 15 days) inhibits tumor growth in Ba/F3 KIF5B-RET G810R and Ba/F3 KIF5B-RET V804M CDX mice models[1].

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

Animal Model: Female BALB/c nude mice (6-8 weeks) subcutaneously implanted with KIF5B-RET tumors[1]
Dosage: 3, 10 and 30 mg/kg
Administration: p.o., BID for 28 days
Result: 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.
Animal Model: Female BALB/c nude mice (6-8 weeks) subcutaneously implanted with CCDC6-RET V804M tumors[1]
Dosage: 3, 10 and 30 mg/kg
Administration: p.o., BID for 28 days
Result: 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.
Animal Model: Female BALB/c nude mice (6-8 weeks) intracranially implanted with CCDC6-RET tumors into the brain[1]
Dosage: 10 and 30 mg/kg
Administration: p.o., BID for 90 days
Result: 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.
Animal Model: Female BALB/c nude mice (6-8 weeks) subcutaneously injected with Ba/F3 KIF5B-RET G810R cells[1]
Dosage: 10 and 30 mg/kg
Administration: p.o., BID for 15 days
Result: 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.
Animal Model: Female BALB/c nude mice (6-8 weeks) subcutaneously injected with Ba/F3 KIF5B-RET V804M cells[1]
Dosage: 10 mg/kg
Administration: p.o., BID for 14 days
Result: 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.
Molecular Weight

496.56

Formula

C27H28N8O2
CAS No.
SMILES

CCOC1=CN2NC3=NN=CC3=C2C(C4=CC=C(N5CC6N(C(C6)C5)CC7=CN=C(C=C7)OC)N=C4)=C1
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Keywords:

APS031182598870-24-5APS 03118APS-03118ERKRETExtracellular signal regulated kinasesRET-G810RET-V804RET-L730RET-Y806ShcERK1/2LC2/ad cellTT-RET C634W cellsKIF5B-RET PDXCCDC6-RET V804 M PDXintracranial CCDC6-RET metastasis modelSRI-resistant RET-driven cancerInhibitorinhibitorinhibit

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