Nurix Therapeutics, Inc. announced the publication of a manuscript in the journal Science titled: ?Kinase Impaired BTK Mutations Are Susceptible to Clinical Stage BTK and IKZF1/3 Degrader NX-2127? that elucidates a previously unappreciated oncogenic scaffold function of BTK responsible for clinical resistance to enzymatic inhibitors and shows that NX-2127, a potent targeted protein degrader with differentiated activity against BTK and IKZF1/3, can overcome this resistance across a broad range of acquired mutations. The article describes studies designed to investigate and characterize acquired BTK mutations that confer resistance to BTK inhibitors commonly used in the treatment of B-cell malignancies.

The research identified a new class of kinase impaired mutants that render BTK enzymatically inactive and revealed that these mutations create novel protein-protein interactions that can propagate biochemical signaling through a process known as scaffolding, a nonenzymatic function of the BTK protein that sustains B-cell receptor (BCR) signaling and promotes the growth of malignant B-cells. Importantly, the authors report data demonstrating efficient proteasomal degradation of BTK in the blood of all NX-2127-treated patients with chronic lymphocytic leukemia (CLL), resulting in reduction of BTK enzymatic activity and suppression of BCR signaling regardless of mutational status. The work was carried out by Nurix in collaboration with scientists and clinicians at several prominent cancer research centers, including Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine and the Sloan Kettering Institute at Memorial Sloan Kettering Cancer Center.

A Drug Annotation manuscript published contemporaneously in The Journal of Medicinal Chemistry entitled ?Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of Bruton?s Tyrosine Kinase with Immunomodulatory Activity for the Treatment of Patients with B Cell Malignancies? reports data detailing the discovery and optimization of NX-2127, including characterization of NX-2127?s activity in preclinical tumor models, cross-species pharmacokinetics and in vitro safety which supported the advancement of this molecule into clinical testing. NX-2127 is a novel bifunctional, orally bioavailable, investigational new drug that degrades BTK and cereblon neosubstrates Ikaros (IKZF1) and Aiolos (IKZF3).

NX-2127 is currently being evaluated in a Phase 1 clinical trial in patients with relapsed or refractory B cell malignancies. NX-5948 is an investigational, orally bioavailable, small molecule degrader of BTK that, unlike NX-2127, has been designed to lack cereblon immunomodulatory activity. NX-5948 is currently being evaluated in a Phase 1 clinical trial in patients with relapsed or refractory B cell malignancies.