APS03118 is a potent and selectiv next-generation RET inhibitor with IC50 of 0.095, 1.36, 0.0356 and 0.127 nM for RET WT, RET V804E, RET V804L and RET V804M nM respectively.
APS03118 exhibits potent inhibitory activity against both RET fusions and mutations, with IC50 values predominantly below 1.0 nM, maintains robust efficacy against key resistance-conferring RET mutations, including V804 (gatekeeper), G810 (solvent-front), L730 (roof), and Y806H (hinge).
APS03118 inhibits 2% of the kinase >90% and 6.9% > 65% (S(90)468 = 0.02 and S(65)468 = 0.069) against a panel consisting of 468 WT and mutant human kinases at 100 nM, demonstrates moderate selectivity against FLT3 (8.6-fold) and YES (13.6-fold).
APS03118 exhibits superior potency to both pralsetinib and selpercatinib against RET solvent-front and gatekeeper mutations that confer resistance to RET inhibitors.
APS03118 displays effective antiproliferative activity in the human LC2/ad lung adenocarcinoma carcinoma cell line harboring another oncogenic CCDC6-RET fusion (Ba/F3 CCDC6-RET, IC50=8.38 nM; Ba/F3 CCDC6-RET V804M, IC50=2.88 nM).
APS03118 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, respectively.
APS03118 (10 nM) almost abolished the phosphorylation of RET, Shc and ERK1/2 in thyroid cancer TT cells harboring RET with C634W mutation.
APS03118 (3 -30 mg/kg, twice daily, oral) significantly reduced tumor volumes in CCDC6-RET V804 M model and in the Ba/F3 KIF5B-RET G810R cell xenograft mouse model.