Definition

An orally bioavailable chimeric targeting molecule (CTM) and targeted degrader of Bruton’s tyrosine kinase (BTK), with potential antineoplastic activity. NX-5948 is comprised of a cereblon (CRBN)-binding moiety conjugated, via a linker, to a BTK-binding moiety. Upon oral administration, BTK degrader NX-5948 targets and binds to BTK with its BTK-targeting moiety. Upon binding, the CRBN-binding moiety recruits CRBN, a component of the CRL4-CRBN E3 ubiquitin ligase complex. This catalyzes ubiquitination and proteasome-mediated degradation of BTK, and prevents the activation of the B-cell antigen receptor (BCR) signaling pathway. This prevents both B-cell activation and BTK-mediated activation of downstream survival pathways. This leads to an inhibition of the growth of malignant B-cells that overexpress BTK. NX-5948 does not catalyze the degradation of CRBN neosubstrates and transcription factors Aiolos (IKZF3) and Ikaros (IKZF1), and does not possess immunomodulatory activity. BTK, a member of the src-related BTK/Tec family of cytoplasmic tyrosine kinases, is overexpressed in B-cell malignancies; it plays an important role in B-lymphocyte development, activation, signaling, proliferation and survival. CRBN, the substrate recognition component of the CRL4-CRBN E3 ubiquitin ligase complex, plays a key role in the ubiquitination of certain proteins. NX-5948 may overcome tumor resistance associated with BTK inhibitor-induced resistance mutations. In addition, NX-5948 is able to cross the blood-brain barrier (BBB) and thus potentially useful in the treatment of central nervous system (CNS) metastases.