On February 1, 2024 Nurix Therapeutics, Inc. (Nasdaq: NRIX), a clinical stage biopharmaceutical company developing targeted protein modulation drugs designed to treat patients with cancer and inflammatory diseases, reported 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 (Press release, Nurix Therapeutics, FEB 1, 2024, View Source [SID1234639783]).

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"While BTK inhibitors have positively changed clinical outcomes for patients with B-cell malignancies, the emergence of acquired resistance to these medicines is a growing clinical problem," said Alexey Danilov, M.D., Ph.D. Professor and Co-Director, Toni Stephenson Lymphoma Center, City of Hope National Medical Center. "Identification of the different types of mutations has important implications for the therapeutic sequencing of currently used targeted BTK inhibitors and reinforces the need for the development of novel agents, such as Nurix’s NX-2127 and NX-5948, that have the potential to provide improved mutation-agnostic treatment options for patients."

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.

"These publications represent the first compendium of biochemical, cellular, and clinical evidence that NX-2127 degrades both previously described and newly discovered BTK inhibitor resistance mutations, a novel mechanism of action in the treatment of B-cell malignancies that is associated with meaningful clinical responses," said Gwenn M. Hansen, Ph.D., chief scientific officer of Nurix. "The data described in this publication in Science reinforce the broad utility of the targeted protein degradation mechanism compared to inhibition approaches to more completely block BTK function and potentially other important enzymatic disease targets where development of acquired resistance is an issue."

"The first-in-human trial of NX-2127 is ongoing in patients with relapsed and refractory B-cell malignancies, including CLL. Based on our clinic data, which were recently presented at the 2023 ASH (Free ASH Whitepaper) Annual Meeting, we have also initiated expansion cohorts in patients with diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL)," said Paula O’Connor, M.D., senior vice president of clinical development at Nurix. "With the ability to target BTK inhibitor resistance mutations and achieve clinical responses, we believe that BTK degraders have the potential to become the next dominant class of agents in the significant BTK-targeted therapy field. We look forward to presenting additional clinical data from this program, and from our NX-5948 BTK degrader program, which is also being evaluated in patients with CLL, at future medical meetings."

About NX-2127
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. Additional information on the ongoing clinical trial can be accessed at www.clinicaltrials.gov (NCT04830137).

About NX-5948
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. Additional information on the ongoing clinical trial can be accessed at clinicaltrials.gov (NCT05131022).