Deciphering the Role of BTK Degradation in B Cell Malignancy Treatment

Bruton's tyrosine kinase (BTK) is an essential element in B cell receptor signaling pathways, critical for B cell growth and functionality. The enzyme is also vital for the survival of certain B cell cancers, such as Chronic Lymphocytic Leukemia (CLL). Ibrutinib, a covalent BTK inhibitor, has shown clinical success, but resistance to it can emerge over time, necessitating the development of alternative treatments.

A novel strategy involves the use of Chimeric Targeting Molecules (CTMs), which facilitate the ubiquitination and subsequent degradation of specific proteins via the proteasome. CTMs consist of a ubiquitin ligase binding component (referred to as the "harness"), a chemical linker, and a target binding component (known as the "hook"). The application of CTMs to degrade both wild-type and ibrutinib-resistant BTK variants offers a fresh method of targeting BTK, potentially affecting both its catalytic and other functions.

Researchers have discovered several CTMs capable of inducing BTK degradation in various B cell lines. NRX0492, one such CTM, demonstrated a degradation concentration of 50% BTK (DC50) at less than 1 nM after a 4-hour period. These BTK-targeting CTMs also compromised the viability of the BTK-dependent ABC-DLBCL cell line, TMD8, with an effective concentration of 50% (EC50) of less than 10 nM after 72 hours. Furthermore, they induced the degradation of the ibrutinib-resistant C481S BTK mutant in cells and caused a loss of viability in BTKC481S mutant TMD8 cells, with EC50 values under 10 nM, contrasting with ibrutinib's EC50 of over 1 μM.

Oral administration of NRX0492 to mice resulted in proportional plasma exposure and BTK degradation in B cells from the circulation and spleen. After a single oral dose, at the 6-hour mark, only 11% of BTK remained in mouse splenocytes, compared to the 100% BTK in control mice (statistically significant difference). In a xenograft model with wild-type TMD8 cells, NRX0492 showed tumor growth inhibition (TGI) comparable to ibrutinib, with 54.4% and 55.8% TGI, respectively, over a period of 23 days of daily oral dosing. In a xenograft model with the BTKC481S mutation, NRX0492 outperformed ibrutinib, with a TGI of 51.3% versus 15.2%.

Preclinical studies on the safety and toxicity of BTK CTMs are underway to guide future clinical development plans. The degradation of BTK through CTMs could present a new therapeutic strategy for B cell malignancies, especially in cases of resistance to ibrutinib.

The disclosures section indicates that multiple individuals are employed by Nurix Therapeutics, suggesting a potential conflict of interest related to the research findings.