NX-2127 (Zelebrudomide) is a hetero-bifunctional, orally active PROTAC that induces the degradation of BTK and IKZF3 ubiquitination and proteasomal degradation in cells through recruitment of cereblon (CRBN).
NX-2127 degrades BTK in multiple B cell lymphoma lines with DC50 values in the range of 1-13 nM.
NX-2127 displays efficient cellular degradation yet binds to WT and mutant BTK with affinities that render covalent and noncovalent BTK inhibitors ineffective.
NX-2127 drives cellular ternary complex formation between BTK and CRBN by inducing positive cooperativity in both WT and acquired resistance mutant settings.
NX-2127 induces potent degradation of C481S, T474I, V416L, and L528W-mutant BTK and suppresses activation marker expression on cells harboring these mutations.
NX-2127 demonstrates oral bioavailability across pre-clinical species and shows robust tumor growth inhibition in WT and mutant mouse models of lymphoma upon once daily PO dosing.