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 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].
In Vitro, APS03118 (compound 5) shows markedly superior activity against the solvent-front RET G810 mutation compared to Selpercatinib and Pralsetinib [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].
References:
[1]. Zhong J, et al. Discovery of APS03118, a Potent and Selective Next-Generation RET Inhibitor with a Novel Kinase Hinge Scaffold. J Med Chem. 2025 Sep 25;68(18):19536-19553.
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].
In Vitro, APS03118 (compound 5) shows markedly superior activity against the solvent-front RET G810 mutation compared to Selpercatinib and Pralsetinib [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].
References:
[1]. Zhong J, et al. Discovery of APS03118, a Potent and Selective Next-Generation RET Inhibitor with a Novel Kinase Hinge Scaffold. J Med Chem. 2025 Sep 25;68(18):19536-19553.