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

Bruton’s tyrosine kinase (BTK),
a member of the
TEC family
of kinases, is an essential effector of B-cell receptor (BCR) signaling.
Chronic activation of BTK-mediated BCR signaling is a hallmark of
many hematological malignancies, which makes it an attractive therapeutic
target. Pharmacological inhibition of BTK enzymatic function is now
a well-proven strategy for the treatment of patients with these malignancies.
We report the discovery and characterization of NX-2127, a BTK degrader
with concomitant immunomodulatory activity. By design, NX-2127 mediates
the degradation of transcription factors IKZF1 and IKZF3 through molecular
glue interactions with the cereblon E3 ubiquitin ligase complex. NX-2127
degrades common BTK resistance mutants, including BTKC481S. NX-2127 is orally bioavailable, exhibits in vivo degradation across species, and demonstrates efficacy in preclinical
oncology models. NX-2127 has advanced into first-in-human clinical
trials and achieves deep and sustained degradation of BTK following
daily oral dosing at 100 mg.