TRK xDFG mutations trigger a sensitivity switch from type I ...
WEBIn this paper, we study how TRK xDFG mutations can mediate resistance to 2 nd -generation TRK inhibitors. The xDFG residue maps immediately N-terminal to the DFG motif, an evolutionary conserved triad across most kinases whose orientation defines the conformational states adopted by kinases (15).
Selective type II TRK inhibitors overcome xDFG mutation ...
WEBFeb 1, 2024 · Based on the recent studies that TRK xDFG mutations stabilize the DFG-out inactive conformation and sensitize these mutant kinases to type II inhibitors 28, 29, we intended to switch this type I inhibitor 21 to a type II inhibitor to overcome xDFG resistances.
NTRK fusion-positive cancers and TRK inhibitor therapy - Nature
WEBOct 17, 2018 · The resistance mutations can result in amino acid substitutions involving the solvent front, activation loop xDFG motif or so-called gatekeeper residue of TRKA or TRKC (Fig. 5a). No mutations in...
Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in ...
WEBFeb 21, 2018 · The xDFG mutations occur within a portion of the kinase-activation loop and sterically interfere with binding of the drug.
TRK xDFG Mutations Trigger a Sensitivity Switch from Type I ...
WEBComputational modeling and biochemical assays showed that TRKA G667 and TRKC G696 xDFG substitutions reduce drug binding by generating steric hindrance. Concurrently, these mutations stabilize the inactive (DFG-out) conformations of the kinases, thus sensitizing these kinases to type II TRK inhibitors.
NTRK kinase domain mutations in cancer variably impact ...
WEBDec 16, 2020 · Mutations at this position (G667) in the NTRK kinase domain are classified as xDFG with the ‘x’ indicating the position immediately amino-terminal to the DFG motif.
TRK inhibitors in TRK fusion-positive cancers - PMC
WEBNov 18, 2019 · In the face of widespread disease progression, a second-generation TRK inhibitor trial could be considered for tumours that harbour on-target resistance, as evidence by the acquisition of solvent front, gatekeeper or xDFG TRKA/B/C substitutions.
Structure-Based Optimization of the Third Generation Type II ...
WEBThe solvent-front (SF), gatekeeper, and xDFG motif mutations of tropomyosin receptor kinase (TRK) mediating acquired resistance of larotrectinib and entrectinib represent an unmet clinical need. To date, no effective drugs are …
Discovery of the First Highly Selective and Broadly Effective ...
WEBApr 15, 2022 · Novel therapeutics for patients with xDFG resistance mutations are urgently needed. We report the first highly selective macrocycle-based potent type II TRK inhibitor, 7b, that exhibits high inhibitory potency toward various TRK fusion protein variants as …
Discovery of Next-Generation Tropomyosin Receptor Kinase ...
WEBOct 28, 2021 · However, xDFG mutations remain insensitive to second-generation macrocyclic TRKIs selitrectinib (3) and repotrectinib (4) designed to overcome the resistance mediated by solvent-front and gatekeeper mutations. Here, we report the structure-based drug design and discovery of a next-generation TRKI.
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