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

• Published in: Journal of medicinal chemistry 2024-02, Vol.67 (4), p.2321-2336
• Main Authors: Robbins, Daniel W., Noviski, Mark A., Tan, Ying Siow, Konst, Zef A., Kelly, Aileen, Auger, Paul, Brathaban, Nivetha, Cass, Robert, Chan, Ming Liang, Cherala, Ganesh, Clifton, Matthew C., Gajewski, Stefan, Ingallinera, Timothy G., Karr, Dane, Kato, Daisuke, Ma, Jun, McKinnell, Jenny, McIntosh, Joel, Mihalic, Jeff, Murphy, Brent, Panga, Jaipal Reddy, Peng, Ge, Powers, Janine, Perez, Luz, Rountree, Ryan, Tenn-McClellan, Austin, Sands, Arthur T., Weiss, Dahlia R., Wu, Jeffrey, Ye, Jordan, Guiducci, Cristiana, Hansen, Gwenn, Cohen, Frederick
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c01007

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.