Abstract 7003: NX-5948 is a CNS-penetrant catalytic Bruton’s tyrosine kinase (BTK) degrader that breaks established design rules for CNS drugs
Authors: Wylie Palmer, Mark Noviski, Paul Auger, Karthik Arumugam, Danielle Bautista, Nivetha Brathaban, Robert Cass, Ming Liang Chan, Ganesh Cherala, Philip Keyes, Aishwarya Kumar, Saloni Malla, Mitchell Lavarias, Filippo Marchioni, Jenny McKinnell, Jun Ma, Ryan Rountree, May Tan, Alexandra Trotier, Sarah Whelan, Davorka Messmer, Frederick Cohen, Gwenn M. Hansen
Journal: Cancer Research (2025)

Abstract NX-5948 is a targeted protein degrader of Bruton’s Tyrosine Kinase (BTK) in Phase 1 clinical development for the treatment of B cell malignancies. Heterobifunctional degraders, such as NX-5948, occupy beyond Rule-of-Five chemical space where established guidelines for physicochemical properties associated with drug-likeness cannot easily be applied. In contrast to approved central nervous system (CNS) drugs, NX-5948 exceeds several recognized chemical property metrics, such as molecular weight, polar surface area, and hydrogen-bond donor count. In addition, NX-5948 does not conform with in vitro permeability and transporter efflux ratio guidelines that would predict for CNS penetration. Despite these unfavorable properties, NX-5948 shows CNS exposure in preclinical models. As a bifunctional degrader with an event-driven mode of action, NX-5948 induces potent degradation of BTK in primary human B cells and malignant B cells. By performing a series of in vitro experiments measuring cellular partitioning and degradation kinetics, we calculated the catalytic efficiency of NX-5948 and demonstrate that one degrader molecule can promote degradation of thousands of copies of target protein. This enables a very low concentration of free drug to sustain pharmacodynamic activity and efficacy in vivo. NX-5948 shows dose-dependent brain exposure in rodents with an unbound brain-to-plasma partition coefficient, or Kp, uu, value consistent with CNS penetration. Additionally, NX-5948 degrades BTK in microglia in naive mice and rats with intact blood-brain barriers. NX-5948 also degrades BTK in intracranially-implanted tumor cells and extends survival in an intracranial TMD8 mouse model of CNS lymphoma. In the clinic, NX-5948 is detectable in cerebrospinal fluid of patients with CNS-involved B-cell malignancies, with concentrations that exceed the minimum free plasma level that correlates with BTK degradation. NX-5948 has also demonstrated clinically meaningful responses in patients with primary CNS lymphoma or chronic lymphocytic leukemia with CNS involvement (Hansen, G., AACR San Diego, 2024; Linton, K., EHA Hybrid Congress, Madrid, Spain, 2024), supporting the therapeutic potential of NX-5948 in B-cell malignancies with CNS involvement. Citation Format: Wylie Palmer, Mark Noviski, Paul Auger, Karthik Arumugam, Danielle Bautista, Nivetha Brathaban, Robert Cass, Ming Liang Chan, Ganesh Cherala, Philip Keyes, Aishwarya Kumar, Saloni Malla, Mitchell Lavarias, Filippo Marchioni, Jenny McKinnell, Jun Ma, Ryan Rountree, May Tan, Alexandra Trotier, Sarah Whelan, Davorka Messmer, Frederick Cohen, Gwenn M. Hansen. NX-5948 is a CNS-penetrant catalytic Bruton’s tyrosine kinase (BTK) degrader that breaks established design rules for CNS drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7003.