Avanti Biosciences, Inc., 3210 Merryfield Row, San Diego, CA 92121, USA.
Department of Molecular Biology, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA.
Int J Mol Sci. 2024 Nov 4;25(21):11827. doi: 10.3390/ijms252111827.
The persistent challenge of idiopathic pulmonary fibrosis (IPF), characterized by disease progression and high mortality, underscores the urgent need for innovative therapeutic strategies. We have developed a novel small molecule-catechin derivative ABI-171-selectively targeting dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) and proviral integration site for Moloney murine leukemia virus 1 (PIM1) kinases, crucial in the pathogenesis of fibrotic processes. We employed the Bleomycin-induced (intratracheal) mouse model of pulmonary fibrosis (PF) to evaluate the therapeutic efficacy of ABI-171. Mice with induced PF were treated QD with ABI-171, either prophylactically or therapeutically, using oral and intranasal routes. Pirfenidone (100 mg/kg, TID) and Epigallocatechin gallate (EGCG, 100 mg/kg, QD), a natural catechin currently in a Phase 1 clinical trial, were used as reference compounds. ABI-171, administered prophylactically, led to a significant reduction in hydroxyproline levels and fibrotic tissue formation compared to the control group. Treatment with ABI-171 improved body weight, indicating mitigation of disease-related weight loss. Additionally, ABI-171 demonstrated anti-inflammatory activity, reducing lymphocyte and neutrophil infiltration. In the therapeutic setting, ABI-171, administered 7 days post-induction, reduced mortality rates ( = 0.04) compared with the bleomycin and EGCG control groups. ABI-171 also ameliorated the severity of lung injuries assessed by improved Masson's trichrome scores when administered both orally and intranasally. ABI-171 significantly decreases bleomycin-induced PF and improves survival in mice, showcasing promising therapeutic potential beyond current medications like pirfenidone and EGCG for patients with IPF. Based on these results, further studies with ABI-171 are ongoing in preclinical studies.
特发性肺纤维化 (IPF) 一直是一个难题，其特征是疾病进展和高死亡率，这突显了迫切需要创新的治疗策略。我们开发了一种新型的小分子儿茶素衍生物 ABI-171，它可以选择性地靶向双特异性酪氨酸磷酸化调节激酶 1A (DYRK1A) 和 Moloney 鼠白血病病毒 1 前病毒整合位点 (PIM1) 激酶，这些激酶在纤维化过程的发病机制中至关重要。我们使用博来霉素诱导的 (气管内) 肺纤维化 (PF) 小鼠模型来评估 ABI-171 的治疗效果。使用口服和鼻腔途径，对诱导 PF 的小鼠进行 ABI-171 的预防性或治疗性 QD 治疗。吡非尼酮 (100mg/kg，TID) 和表没食子儿茶素没食子酸酯 (EGCG，100mg/kg，QD)，一种目前正在进行 1 期临床试验的天然儿茶素，被用作参考化合物。与对照组相比，预防性给予 ABI-171 可显著降低羟脯氨酸水平和纤维化组织形成。用 ABI-171 治疗可改善体重，表明减轻了与疾病相关的体重减轻。此外，ABI-171 表现出抗炎活性，减少淋巴细胞和中性粒细胞浸润。在治疗性设置中，与博来霉素和 EGCG 对照组相比，在诱导后 7 天给予 ABI-171 可降低死亡率 ( = 0.04)。当口服和鼻腔给予 ABI-171 时，它还改善了由改良的马松三色评分评估的肺损伤的严重程度。ABI-171 可显著降低博来霉素诱导的 PF 并提高小鼠的存活率，为 IPF 患者提供了比目前的药物如吡非尼酮和 EGCG 更有前途的治疗潜力。基于这些结果，正在进行用 ABI-171 进行的临床前研究。
