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. 2024 Feb 22;67(4):2321-2336. doi: 10.1021/acs.jmedchem.3c01007.
Daniel W Robbins  1 ,  Mark A Noviski  1 ,  Ying Siow Tan  1 ,  Zef A Konst  1 ,  Aileen Kelly  1 ,  Paul Auger  1 ,  Nivetha Brathaban  1 ,  Robert Cass  1 ,  Ming Liang Chan  1 ,  Ganesh Cherala  1 ,  Matthew C Clifton  1 ,  Stefan Gajewski  1 ,  Timothy G Ingallinera  1 ,  Dane Karr  1 ,  Daisuke Kato  1 ,  Jun Ma  1 ,  Jenny McKinnell  1 ,  Joel McIntosh  1 ,  Jeff Mihalic  1 ,  Brent Murphy  1 ,  Jaipal Reddy Panga  1 ,  Ge Peng  1 ,  Janine Powers  1 ,  Luz Perez  1 ,  Ryan Rountree  1 ,  Austin Tenn-McClellan  1 ,  Arthur T Sands  1 ,  Dahlia R Weiss  1 ,  Jeffrey Wu  1 ,  Jordan Ye  1 ,  Cristiana Guiducci  1 ,  Gwenn Hansen  1 ,  Frederick Cohen  1
Affiliations
  • 1. Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States.
PMID: 38300987 DOI: 10.1021/acs.jmedchem.3c01007
Abstract

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.

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