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 NTRK 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 19 and 20 demonstrated potent antiproliferative activities against Ba/F3-LMNA-NTRK1G667C 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; Dmax > 90%), while sparing the wild-type protein. Further in vivo assay displayed that 20 effectively inhibited tumor growth with no apparent toxicity in the Ba/F3-LMNA-NTRK1G667C 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.