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.