دورية أكاديمية
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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.

التفاصيل البيبلوغرافية
العنوان: 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.
المؤلفون: Robbins DW; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Noviski MA; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Tan YS; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Konst ZA; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Kelly A; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Auger P; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Brathaban N; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Cass R; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Chan ML; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Cherala G; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Clifton MC; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Gajewski S; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Ingallinera TG; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Karr D; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Kato D; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Ma J; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., McKinnell J; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., McIntosh J; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Mihalic J; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Murphy B; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Panga JR; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Peng G; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Powers J; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Perez L; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Rountree R; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Tenn-McClellan A; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Sands AT; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Weiss DR; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Wu J; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Ye J; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Guiducci C; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Hansen G; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States., Cohen F; Nurix Therapeutics, Inc., 1700 Owens St., San Francisco, California 94158, United States.
المصدر: Journal of medicinal chemistry [J Med Chem] 2024 Feb 22; Vol. 67 (4), pp. 2321-2336. Date of Electronic Publication: 2024 Feb 01.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
مواضيع طبية MeSH: Protein-Tyrosine Kinases* , Protein Kinase Inhibitors*/adverse effects, Humans ; Agammaglobulinaemia Tyrosine Kinase ; Signal Transduction
مستخلص: 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 BTK C481S . 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.
المشرفين على المادة: EC 2.7.10.2 (Agammaglobulinaemia Tyrosine Kinase)
EC 2.7.10.1 (Protein-Tyrosine Kinases)
0 (Protein Kinase Inhibitors)
تواريخ الأحداث: Date Created: 20240201 Date Completed: 20240223 Latest Revision: 20240223
رمز التحديث: 20240223
DOI: 10.1021/acs.jmedchem.3c01007
PMID: 38300987
قاعدة البيانات: MEDLINE
الوصف
تدمد:1520-4804
DOI:10.1021/acs.jmedchem.3c01007