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Discovery of DNL343: A Potent, Selective, and Brain-Penetrant eIF2B Activator Designed for the Treatment of Neurodegenerative Diseases
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-03-21 , DOI: 10.1021/acs.jmedchem.3c02422
Robert A Craig 1 , Javier De Vicente 1 , Anthony A Estrada 1 , Jianwen A Feng 1 , Katrina W Lexa 1 , Mark J Canet 1 , William E Dowdle 1 , Rebecca I Erickson 1 , Brittany N Flores 1 , Patrick C G Haddick 1 , Lesley A Kane 1 , Joseph W Lewcock 1 , Nathan J Moerke 1 , Suresh B Poda 1 , Zachary Sweeney 1 , Ryan H Takahashi 1 , Vincent Tong 1 , Jing Wang 1 , Ernie Yulyaningsih 1 , Hilda Solanoy 1 , Kimberly Scearce-Levie 1 , Pascal E Sanchez 1 , Liwei Tang 2 , Musheng Xu 2 , Rui Zhang 2 , Maksim Osipov 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-03-21 , DOI: 10.1021/acs.jmedchem.3c02422
Robert A Craig 1 , Javier De Vicente 1 , Anthony A Estrada 1 , Jianwen A Feng 1 , Katrina W Lexa 1 , Mark J Canet 1 , William E Dowdle 1 , Rebecca I Erickson 1 , Brittany N Flores 1 , Patrick C G Haddick 1 , Lesley A Kane 1 , Joseph W Lewcock 1 , Nathan J Moerke 1 , Suresh B Poda 1 , Zachary Sweeney 1 , Ryan H Takahashi 1 , Vincent Tong 1 , Jing Wang 1 , Ernie Yulyaningsih 1 , Hilda Solanoy 1 , Kimberly Scearce-Levie 1 , Pascal E Sanchez 1 , Liwei Tang 2 , Musheng Xu 2 , Rui Zhang 2 , Maksim Osipov 1
Affiliation
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Eukaryotic translation initiation factor 2B (eIF2B) is a key component of the integrated stress response (ISR), which regulates protein synthesis and stress granule formation in response to cellular insult. Modulation of the ISR has been proposed as a therapeutic strategy for treatment of neurodegenerative diseases such as vanishing white matter (VWM) disease and amyotrophic lateral sclerosis (ALS) based on its ability to improve cellular homeostasis and prevent neuronal degeneration. Herein, we report the small-molecule discovery campaign that identified potent, selective, and CNS-penetrant eIF2B activators using both structure- and ligand-based drug design. These discovery efforts culminated in the identification of DNL343, which demonstrated a desirable preclinical drug profile, including a long half-life and high oral bioavailability across preclinical species. DNL343 was progressed into clinical studies and is currently undergoing evaluation in late-stage clinical trials for ALS.
中文翻译:
DNL343 的发现:一种强效、选择性、脑渗透性 eIF2B 激活剂,专为治疗神经退行性疾病而设计
真核翻译起始因子 2B (eIF2B) 是综合应激反应 (ISR) 的关键组成部分,可调节蛋白质合成和应激颗粒形成以应对细胞损伤。 ISR 的调节已被提议作为治疗神经退行性疾病的治疗策略,例如白质消失 (VWM) 疾病和肌萎缩侧索硬化症 (ALS),基于其改善细胞稳态和预防神经元变性的能力。在此,我们报告了小分子发现活动,该活动利用基于结构和配体的药物设计鉴定了有效、选择性和 CNS 渗透性 eIF2B 激活剂。这些发现工作最终导致了 DNL343 的鉴定,该药物表现出了理想的临床前药物特征,包括跨临床前物种的长半衰期和高口服生物利用度。 DNL343已进入临床研究,目前正在进行ALS后期临床试验的评估。
更新日期:2024-03-21
中文翻译:
![](https://scdn.x-mol.com/jcss/images/paperTranslation.png)
DNL343 的发现:一种强效、选择性、脑渗透性 eIF2B 激活剂,专为治疗神经退行性疾病而设计
真核翻译起始因子 2B (eIF2B) 是综合应激反应 (ISR) 的关键组成部分,可调节蛋白质合成和应激颗粒形成以应对细胞损伤。 ISR 的调节已被提议作为治疗神经退行性疾病的治疗策略,例如白质消失 (VWM) 疾病和肌萎缩侧索硬化症 (ALS),基于其改善细胞稳态和预防神经元变性的能力。在此,我们报告了小分子发现活动,该活动利用基于结构和配体的药物设计鉴定了有效、选择性和 CNS 渗透性 eIF2B 激活剂。这些发现工作最终导致了 DNL343 的鉴定,该药物表现出了理想的临床前药物特征,包括跨临床前物种的长半衰期和高口服生物利用度。 DNL343已进入临床研究,目前正在进行ALS后期临床试验的评估。