Discovery of Novel Bifunctional Agents as Potent TRK Inhibitors and Degraders against xDFG Mutation Resistance

Despite the clinical success of tropomyosin receptor kinases (TRKs) inhibitors in <i>NTRK</i> fusion-positive cancers, prolonged administration has resulted in acquired resistance, particularly xDFG mutations, for which no approved therapies are available. Herein, we first presented a series of bifunctional agents as potent TRK inhibitors and degraders featuring a novel 5-amino-4-carbamoylpyrazole scaffold. The representative compounds <b>19</b> and <b>20</b> demonstrated potent antiproliferative activities against Ba/F3-LMNA-NTRK1^<i>G667C</i> cells with IC₅₀ values of 0.29 and 2.48 nM, respectively, and induced pronounced TRKA G667C degradation (DC₅₀ = 5.86 and 24.69 nM; <i>D</i>_max > 90%), while sparing the wild-type protein. Further <i>in vivo</i> assay displayed that <b>20</b> effectively inhibited tumor growth with no apparent toxicity in the Ba/F3-LMNA-NTRK1^<i>G667C</i> xenograft model. Overall, these findings indicated that, unlike conventional inhibitors, such bifunctional agents represent the first class of monovalent small molecules capable of effectively degrading TRK xDFG mutants, providing valuable insights into overcoming TRK xDFG-mediated clinical resistance.