LIT-927

LIT-927 is a highly selective and orally active C-X-C chemokine ligand 12 (CXCL12) neutraligand that effectively inhibits the interaction between the CXCL12 and its receptor CXCR4, with a binding affinity K_i value of 267nM^[1]. CXCL12 is a key chemokine involved in inflammation, immune cell recruitment, and tissue homeostasis, exerting biological functions through binding to receptors CXCR4/CXCR7^[2]. By blocking CXCL12, LIT-927 reduces inflammation and has been used in the treatment and research of allergic airway diseases and autoimmune disorders^[3,4].

In vitro, treatment of MRL/lpr mouse splenocytes with LIT-927 (0-20μM) for 24h downregulated the overexpression of activation markers CD25 and CD86 on CD4⁺ T cells and reduced CD40 expression on B cells in a dose-dependent manner^[5]. LIT-927 (10, 30μM) treatment of human pulmonary artery smooth muscle cells (PA-SMCs) for 24h inhibited PA-SMC migration in a concentration-dependent manner^[6]. LIT-927 (0.5μM) treatment of human glioblastoma U-87 MG cells for 24h suppressed temozolomide (TMZ)-induced phosphorylation of ERK and NF-κB^[7].

In vivo, intranasal administration of LIT-927 (197ng/mL; 10μL) to house dust mite-sensitized C57Bl/6 mice for 2 weeks significantly reduced respiratory symptom scores, effectively inhibited pericyte migration, and alleviated airway smooth muscle thickening^[8]. Intraperitoneal injection of LIT-927 (100mg/kg/day) for 2 weeks in monocrotaline (MCT)-induced pulmonary artery hypertensive rats significantly reduced mean pulmonary arterial pressure (mPAP), total pulmonary vascular resistance (TPVR), and right ventricular hypertrophy (Fulton index)^[6].

References:
[1] REGENASS P, ABBOUD D, DAUBEUF F, et al. Discovery of a locally and orally active CXCL12 neutraligand (LIT-927) with anti-inflammatory effect in a murine model of allergic airway hypereosinophilia[J]. Journal of Medicinal Chemistry, 2018, 61(17): 7671-7686.
[2] MINAMI H, NAGAHARU K, NAKAMORI Y, et al. CXCL12-CXCR4 axis is required for contact-mediated human B lymphoid and plasmacytoid dendritic cell differentiation but not T lymphoid generation[J]. The Journal of Immunology, 2017, 199(7): 2343-2355.
[3] JANSSENS R, STRUYF S, PROOST P. The unique structural and functional features of CXCL12[J]. Cellular & Molecular Immunology, 2018, 15(4): 299-311.
[4] LU L, LI J, JIANG X, et al. CXCR4/CXCL12 axis: "old" pathway as "novel" target for anti-inflammatory drug discovery[J]. Medicinal Research Reviews, 2024, 44(3): 1189-1220.
[5] SCHALL N, DAUBEUF F, MARSOL C, et al. A selective neutraligand for CXCL12/SDF-1α with beneficial regulatory functions in MRL/Lpr lupus prone mice[J]. Frontiers in Pharmacology, 2021, 12: 752194.
[6] BORDENAVE J, THUILLET R, TU L, et al. Neutralization of CXCL12 attenuates established pulmonary hypertension in rats[J]. Cardiovascular Research, 2020, 116(3): 686-697.
[7] CHIANG I T, LIU Y C, LIU H S, et al. Regorafenib reverses temozolomide-induced CXCL12/CXCR4 signaling and triggers apoptosis mechanism in glioblastoma[J]. Neurotherapeutics, 2022, 19(2): 616-634.
[8] BIGNOLD R, SHAMMOUT B, ROWLEY J E, et al. Chemokine CXCL12 drives pericyte accumulation and airway remodeling in allergic airway disease[J]. Respiratory Research, 2022, 23: 183.

LIT-927是一种能有效抑制C-X-C趋化因子12（CXCL12）与受体CXCR4相互作用，且具有高效选择性和口服活性的CXCL12中和配体，结合亲和力K_i值为267nM^[1]。CXCL12是一种在炎症、免疫细胞招募和组织稳态中起关键作用的趋化因子，通过与受体CXCR4/CXCR7结合发挥生物学功能^[2]。通过阻断CXCL12，LIT-927可以减少炎症，已被用于过敏性呼吸道疾病和自身免疫性疾病等的治疗和研究^[3,4]。

在体外，LIT-927（0-20μM）处理MRL/lpr小鼠脾脏细胞24h，以剂量依赖形式下调了CD4⁺ T细胞表面活化标志物CD25和CD86的过度表达，并降低了B细胞表面CD40的表达^[5]。LIT-927（10, 30μM）处理人肺动脉平滑肌细胞（PA-SMCs）24h，浓度依赖地抑制了PA-SMCs的迁移^[6]。LIT-927（0.5μM）处理人胶质母细胞瘤U-87 MG细胞24h，抑制了由替莫唑胺（TMZ）诱导的ERK和NF-κB磷酸化^[7]。

在体内，对屋尘螨致敏的C57Bl/6小鼠经鼻内给药LIT-927（197ng/mL; 10μL）治疗，2周后显著降低了呼吸道症状评分，有效地抑制了周细胞迁移并减轻了气道平滑肌增厚^[8]。LIT-927（100mg/kg/day）通过腹腔注射治疗monocrotaline（MCT）诱导的肺动脉高压大鼠2周，显著降低了平均肺动脉压（mPAP）、总肺血管阻力（TPVR）和右心室肥厚指数（Fulton index）^[6]。