NX-5948: Oral, CNS-penetrant BTK degrader

NX-5948 is an oral, CNS-penetrant, small molecule degrader of Bruton’s tyrosine kinase (BTK) being evaluated in chronic lymphocytic leukemia (CLL), non-Hodgkin’s lymphoma (NHL), and Waldenström macroglobulinemia (WM).

Scientific rationale

BTK is a master regulator of B-cell activity and is a clinically validated target for hematologic malignancies. While BTK inhibitors have shown clinical success, drug resistance often emerges due to acquired mutations in BTK.

By removing BTK rather than merely inhibiting its activity, NX-5948 may circumvent both kinase domain mutations and scaffolding-mediated resistance mutations to provide more durable responses. Additionally, its brain penetration suggests potential for treating challenging CNS-involved leukemias and lymphomas.

Zelebrudomide (NX-2127): Oral dual degrader of BTK and cereblon neosubstrates

Zelebrudomide is an oral small molecule dual degrader targeting Bruton’s tyrosine kinase (BTK) and the cereblon neosubstrates IKZF1 (Ikaros) and IKZF3 (Ailos), which are implicated in B and T cell activity. Zelebrudomide is being evaluated in patients with B-cell malignancies with a focus on aggressive forms of non-Hodgkin lymphoma (NHL).

Scientific rationale

B-cell malignancies often rely on multiple signaling pathways for growth and survival. Two key pathways include:

1. BTK: A master regulator of B-cell activity. Aberrant BTK signaling can drive malignant B-cell proliferation.
2. IKZF1/3: These transcription factors play crucial roles in B-cell development and function.

Importantly, IKZF1/3 also represses proinflammatory cytokine expression from T cells. This dual role of IKZF1/3 in malignant B cells and T cells provides a unique opportunity for therapeutic intervention. By combining BTK degradation with cereblon-mediated immunomodulatory activity, zelebrudomide aims to provide enhanced therapeutic benefit across a spectrum of B-cell malignancies.

NX-1607: Novel CBL-B inhibitor for immuno-oncology

NX-1607 is a first-in-class, small molecule inhibitor of Casitas B-lineage lymphoma proto-oncogene-b (CBL-B), an E3 ligase that acts as a critical checkpoint in the immune system. This innovative compound is being developed as part of Nurix’s immuno-oncology program and is currently being evaluated in advanced malignancies.

Scientific rationale

CBL-B plays a crucial role in regulating immune cell function:

1. In the context of cancer, CBL-B acts as a brake on the immune system by negatively regulating T cell activation, inhibiting NK cell activity, and suppressing overall immune responses.
2. CBL-B achieves this immunosuppressive effect through the degradation of specific inhibitory signaling proteins downstream of the T cell receptor.
3. CBL-B operates in immune cells and the tumor microenvironment, making it a compelling immuno-oncology target.

Importantly, IKZF1/3 also represses proinflammatory cytokine expression from T cells. This dual role of IKZF1/3 in malignant B cells and T cells provides a unique opportunity for therapeutic intervention. By combining BTK degradation with cereblon-mediated immunomodulatory activity, zelebrudomide aims to provide enhanced therapeutic benefit across a spectrum of B-cell malignancies.