NX-5948

NX-5948 (BTK-IN-24) is an orally active chimeric targeting molecule (CTM) that induces specific BTK protein degradation by the cereblon E3 ligase (CRBN) complex without degradation of other cereblon neo-substrates. NX-5948 mediates potent anti-inflammatory activity via BTK degradation with resultant inhibition of B cell activation. NX-5948 exhibits potent tumor growth inhibition in TMD8 xenograft models that contain either wild-type BTK or BTKi-resistant mutations. NX-5948 is efficacious in a mouse collageninduced arthritis (CIA) model. NX-5948 can cross the blood brain barrier (BBB). NX-5948 is a PROTAC composed of the ligand for target protein, a linker, and a cereblon E3 ligase (CRBN) complex (Red: ligand for target protein; Blue: CRBN; Black: linker).

NX-5948 (BTK-IN-24; 0.0001-1000 nM; 4 h) is a potent degrader of BTK in primary human B cells (DC₅₀=0.34 nM) and inhibits BCR signaling^[1]. NX-5948 induces the degradation of BTK (DC₅₀< 1 nM) in lymphoma cell lines and PBMCs^[3].
NX-5948 (10 nM; 0.25, 0.5, 1, 2, 4, 6, 18, 24 h) catalyzes rapid BTK degradation within 1 hour and is complete within 2 hours in Ramos cells^[1].

NX-5948 (BTK-IN-24; 10, 30 mg/kg; po; daily; Day 18 to 36) is efficacious and well-tolerated in a mouse collagen-induced arthritis (CIA) model and suppresses antibody titers and IL-6 cytokine levels^[1].
NX-5948 (3, 10, 30 mg/kg; po) causes dose- and time-dependent reduction in BTK levels in circulating murine and non-human primate, cynomolgus monkey B cells^[1].

References:
[1]. Mark Noviski, et al. NX-5948, a Selective Degrader of BTK, Significantly Reduces Inflammation in a Model of Autoimmune Disease. 2021 Nurix Therapeutics, Inc.
[2]. 4473 Initial Findings from a First-in-Human Phase 1a/b Trial of NX-5948, a Selective Bruton’s Tyrosine Kinase (BTK) Degrader, in Patients with Relapsed/Refractory B Cell Malignancies. Annual Meeting & Exposition, Monday, December 11, 2023.
[3]. Zi Liu, et al. An overview of PROTACs: a promising drug discovery paradigm. Mol Biomed. 2022 Dec 20;3(1):46.