NRX-0492

NRX-0492 is an orally bioavailable, small-molecule targeted protein degrader (PROTAC) designed to eliminate Bruton tyrosine kinase (BTK). It functions by recruiting the E3 ubiquitin ligase cereblon (CRBN) to BTK, leading to its ubiquitination and subsequent proteasomal degradation. Unlike traditional covalent BTK inhibitors (e.g., ibrutinib), NRX-0492 utilizes a noncovalent binding domain, allowing it to remain effective against BTK variants with C481 mutations, which are a common cause of resistance to covalent inhibitors. Developed by Nurix Therapeutics, NRX-0492 has demonstrated potent activity in preclinical models of chronic lymphocytic leukemia (CLL), including patient-derived xenografts. While NRX-0492 itself is often cited as a research lead or tool compound, it represents the chemical precursor or related scaffold for Nurix's clinical-stage BTK degraders such as NX-2127 and NX-5948.