Switch type I to type II TRK inhibitors for combating clinical resistance induced by xDFG mutation for cancer therapy

Structure-Based Optimization of the Third Generation Type II Macrocycle TRK Inhibitors with Improved Activity against Solvent-Front, xDFG, and Gatekeeper Mutations

“…First, the tails derived from commercially available approved type II kinase inhibitors were incorporated to afford compounds 9a – 9d (Table ). However, compounds 9a – 9c displayed dramatically decreased enzymatic potency against TRKA WT and G595R mutant compared to that of 8f , although it inhibited TRKA G667C kinase and BaF3- CD74 - NTRK1 G667C cells with nanomole activity. This was due to that TRKA G595R increases the ATP affinity of the kinase ( K m = 6 μmol/L for TRKA G595R vs 51 μmol/L for TRKA) .…”

Selective type II TRK inhibitors overcome xDFG mutation mediated acquired resistance to the second-generation inhibitors selitrectinib and repotrectinib

“…Our group has also developed several selective TRK inhibitors in recent years 95 , 96 , 97 , 98 , 99 . Compound 15 is a potent ABL (IC 50 = 2.1 nmol/L) and TRKs (IC 50 ranging from 4.4 to 9.4 nmol/L) inhibitor developed in our laboratory 100 .…”

“…Our group also employed hybridization strategy to design a series of 6-(pyrrolidin-1-yl)imidazo[1,2- b ]pyridazine-based type II TRK inhibitors 99 . Compound 21 is a potent type I TRK inhibitor developed by Novartis, which displays high potency towards WT TRKs but weak inhibitory activity against TRKA G667C mutation ( Fig.…”

“…13 A). Subsequently, the hybrid compound 23 was yielded by attaching the N -(3-((4-methyl-piperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)formamide “tail” of 22 and removing the fluorophenyl of 21 that is closed to the xDFG site to avoid steric hindrance 99 . Compound 23 exhibits potent kinase inhibitory activities against WT TRKs (IC 50 ranging from 5.1 to 8.1 nmol/L) as well as TRKA G667C mutation (IC 50 = 16.5 nmol/L), but moderate cellular inhibitory activity against Ba/F3- CD7 4 -TRKA cells (IC 50 = 61.5 nmol/L).…”

“…The docking model of 24 with TRKC suggests that it binds to TRKC in a type II mode with the imidazo[1,2- b ]pyridazine core forming key hydrogen bond with Met620 in the hinge region, the amide group forming two hydrogen bonds with Glu588 in the α -C helix and Asp697 in the DFG motif, respectively ( Fig. 13 B) 99 . Compound 24 provides a potential novel scaffold for the discovery of potent and selective type II TRK inhibitors to overcome TRK clinical resistances.…”