2. Academic Validation
  3. 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

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

Affiliation

  • 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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