8EJB

Bruton's tyrosine kinase in complex with 3-{[4-(1-acetylpiperidin-4-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide

Summary for 8EJB

• Entry DOI: 10.2210/pdb8ejb/pdb
• Descriptor: Tyrosine-protein kinase BTK, 5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-[4-(piperidin-4-yl)anilino]pyrazine-2-carboxamide, 1,2-ETHANEDIOL, ... (6 entities in total)
• Functional Keywords: protein degradation, leukemia, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 32255.81

Authors

Gajewski, S.,Clifton, M.C. (deposition date: 2022-09-16, release date: 2023-02-15, Last modification date: 2024-05-22)

Primary citation

Zhang, D.,Harris, H.M.,Chen, J.,Judy, J.,James, G.,Kelly, A.,McIntosh, J.,Tenn-McClellan, A.,Ambing, E.,Tan, Y.S.,Lu, H.,Gajewski, S.,Clifton, M.C.,Yung, S.,Robbins, D.W.,Pirooznia, M.,Skanland, S.S.,Gaglione, E.,Mhibik, M.,Underbayev, C.,Ahn, I.E.,Sun, C.,Herman, S.E.M.,Noviski, M.,Wiestner, A.
NRX-0492 degrades wild-type and C481 mutant BTK and demonstrates in vivo activity in CLL patient-derived xenografts.
Blood, 141:1584-1596, 2023

PubMed Abstract: Bruton tyrosine kinase (BTK) is essential for B-cell receptor (BCR) signaling, a driver of chronic lymphocytic leukemia (CLL). Covalent inhibitors bind C481 in the active site of BTK and have become a preferred CLL therapy. Disease progression on covalent BTK inhibitors is commonly associated with C481 mutations. Here, we investigated a targeted protein degrader, NRX-0492, that links a noncovalent BTK-binding domain to cereblon, an adaptor protein of the E3 ubiquitin ligase complex. NRX-0492 selectively catalyzes ubiquitylation and proteasomal degradation of BTK. In primary CLL cells, NRX-0492 induced rapid and sustained degradation of both wild-type and C481 mutant BTK at half maximal degradation concentration (DC50) of ≤0.2 nM and DC90 of ≤0.5 nM, respectively. Sustained degrader activity was maintained for at least 24 hours after washout and was equally observed in high-risk (deletion 17p) and standard-risk (deletion 13q only) CLL subtypes. In in vitro testing against treatment-naïve CLL samples, NRX-0492 was as effective as ibrutinib at inhibiting BCR-mediated signaling, transcriptional programs, and chemokine secretion. In patient-derived xenografts, orally administered NRX-0492 induced BTK degradation and inhibited activation and proliferation of CLL cells in blood and spleen and remained efficacious against primary C481S mutant CLL cells collected from a patient progressing on ibrutinib. Oral bioavailability, >90% degradation of BTK at subnanomolar concentrations, and sustained pharmacodynamic effects after drug clearance make this class of targeted protein degraders uniquely suitable for clinical translation, in particular as a strategy to overcome BTK inhibitor resistance. Clinical studies testing this approach have been initiated (NCT04830137, NCT05131022).

PubMed: 36375120
DOI: 10.1182/blood.2022016934

Experimental method

X-RAY DIFFRACTION (1.58 Å)