NX-2127

NX-2127 is a proteolysis-targeting chimera (PROTAC) containing a binding moiety for Bruton's tyrosine kinase (BTK) linked to a cereblon (CRBN) binding moiety.¹ It induces degradation of wild-type BTK (DC₅₀ = 1.9 nM) and BTK mutants containing drug resistance-conferring mutations, including BTK^C481S, BTK^V416L, BTK^T474I, and BTK^L528W in TMD8 diffuse large B cell lymphoma (DLBCL) cells (DC₅₀s = 9.7, 4.2, 2.4, and 1.9 nM, respectively).² NX-2127 also degrades the lymphocyte transcription factors Ikaros family zinc finger protein 1 (IKZF1) and IKZF3 (DC₅₀s = 57 and 36 nM, respectively) and induces T cell activation in primary human T cells stimulated by anti-CD3 and anti-CD28 antibodies.¹ It reduces BTK levels in circulating mouse B cells to 12% of baseline when administered at a dose of 30 mg/kg. NX-2127 (10, 30, and 90 mg/kg per day) induces intratumoral BTK, IKZF1, and IKZF3 degradation in a TMD8 mouse xenograft model. It also reduces tumor growth in mouse xenograft models using TMD8 cells expressing wild-type BTK or BTK^C481S.

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1. Robbins, D.W., Noviski, M.A., Tan, Y.S., et al. 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. J. Med. Chem. 67(4), 2321-2336 (2024).

2. Montoya, S., Bourcier, J., Noviski, M., et al. Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127. Science 383(6682), eadi5798 (2024).

Feng, L., Zhang , H., and Liu, T. Multifaceted roles of IKZF1 gene, perspectives from bench to bedside. Front. Oncol. 14, 1383419 (2024).