NX-5948 is an orally active proteolytic targeting chimera (PROTAC) that is a Bruton’s tyrosine kinase (BTK) degrader[1]. NX-5948 can induce specific BTK protein degradation via the cereblon E3 ligase (CRBN) complex[2]. NX-5948 mediates potent anti-inflammatory activity through BTK degradation, thereby inhibiting B cell activation[3]. In primary human B cells, the half maximal degradation concentration DC50 value of NX-5948 was 0.034nM[4]. NX-5948 can be used to treat B cell malignancies[5].
In vitro, NX-5948 (<1nM) treatment of lymphoma cell lines and peripheral blood mononuclear cells (PBMCs) degraded 50% of cellular BTK[6]. Treatment of BTK-dependent ABC-DLBCL cell line TMD8 cells with NX-5948 (<10nM) for 72h reduced cell viability by 50%[6].
In vivo, oral administration of NX-5948 (10, 30mg/kg) for 18 days to mice model of collagen-induced arthritis (CIA) significantly reduced the mean arthritis score and was well tolerated, and reduced antibody titers and cytokine IL-6 levels[7].
References:
[1] Gao J, Meng C, Yuan V F T. Clinical application of proteolysis targeting chimeras[C]//International Conference on Modern Medicine and Global Health (ICMMGH 2023). SPIE, 2023, 12789: 332-336.
[2] Huynh T, Rodriguez-Rodriguez S, Danilov A V. Bruton Tyrosine Kinase Degraders in B-Cell Malignancies[J]. Molecular Cancer Therapeutics, 2024, 23(5): 619-626.
[3] Huang J, Ma Z, Peng X, et al. Discovery of Novel Potent and Fast BTK PROTACs for the Treatment of Osteoclasts-Related Inflammatory Diseases[J]. Journal of Medicinal Chemistry, 2024, 67(4): 2438-2465.
[4] Rej R K, Allu S R, Roy J, et al. Orally Bioavailable Proteolysis-Targeting Chimeras: An Innovative Approach in the Golden Era of Discovering Small-Molecule Cancer Drugs[J]. Pharmaceuticals, 2024, 17(4): 494.
[5] Mihalic J. First disclosure of Nx-5948, an Oral targeted degrader of Bruton's tyrosine kinase (Btk) for the treatment of B-cell malignancies[C]//266th National Meeting of the American Chemical Society, San Francisco, CA. 2023.
[6] Robbins D W, Noviski M, Rountree R, et al. Nx-5948, a selective degrader of BTK with activity in preclinical models of hematologic and brain malignancies[J]. Blood, 2021, 138: 2251.
[7] Robbins D, Noviski M, Tan M, et al. POS0006 NX-5948, a selective degrader of BTK, significantly reduces inflammation in a model of autoimmune disease[J]. 2021.
NX-5948是一种具口服活性的蛋白水解靶向嵌合体（PROTAC），是布鲁顿酪氨酸激酶（BTK）的降解剂[1]。NX-5948能够通过cereblon E3连接酶（CRBN）复合物诱导特异性BTK蛋白降解[2]。NX-5948通过BTK降解介导有效的抗炎活性，从而抑制B细胞活化[3]。在原代人类B细胞中，NX-5948的半数最大降解浓度 DC50值为0.034nM[4]。NX-5948能够用于治疗B细胞恶性肿瘤[5]。
在体外，NX-5948（<1nM）处理淋巴瘤细胞系和外周血单核细胞（PBMC），降解50%的细胞BTK[6]。NX-5948（<10nM）处理BTK依赖性ABC-DLBCL细胞系TMD8细胞72h，降低了50%的细胞活力[6]。
在体内，NX-5948（10, 30mg/kg）通过口服治疗胶原诱导的关节炎（CIA）模型小鼠18天，显著降低了平均关节炎评分且耐受性良好，降低了抗体滴度和细胞因子IL-6水平[7]。