TRK xDFG mutations trigger a sensitivity switch from type I to II ...
In 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).
TRK xDFG Mutations Trigger a Sensitivity Switch from Type ...
Computational 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.
Selective type II TRK inhibitors overcome xDFG mutation ...
Feb 1, 2024 · However, xDFG (TRKA G667C/A/S, homologous TRKC G696C/A/S) and some double mutations still confer resistance to selitrectinib and repotrectinib, and overcoming these resistances represents a major unmet clinical need. In this review, we summarize the acquired resistance mechanism of the first- and second-generation TRK inhibitors, and firstly ...
Efficacy of Larotrectinib in TRK Fusion–Positive Cancers ...
Feb 21, 2018 · The xDFG mutations occur within a portion of the kinase-activation loop and sterically interfere with binding of the drug.
NTRK fusion-positive cancers and TRK inhibitor therapy
Oct 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...
Selective type II TRK inhibitors overcome xDFG mutation mediated ...
In this review, we summarize the acquired resistance mechanism of the first- and second-generation TRK inhibitors, and firstly put forward the emerging selective type II TRK inhibitors to overcome xDFG mutations mediated resistance.
NTRK kinase domain mutations in cancer variably impact ...
Dec 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.
JND4135, a New Type II TRK Inhibitor, Overcomes TRK xDFG and …
JND4135 displays strong activity against wild-type TRKA/B/C and secondary mutants involving substitutions of the xDFG motif in cells, possesses an extended occupation of TRK protein with a slower binding and dissociation, and shows 81.0% xenograft growth inhibition in animals.
Discovery of the First Highly Selective and Broadly Effective ...
Apr 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 well as wild type.
Selective type II TRK inhibitors overcome xDFG mutation mediated ...
However, xDFG (TRKA G667C/A/S, homologous TRKC G696C/A/S) and some double mutations still confer resistance to selitrectinib and repotrectinib, and overcoming these resistances represents a major unmet clinical need. In this review, we summarize the acquired resistance mechanism of the first- and second-generation TRK inhibitors, and firstly ...
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