在临床开发中筛选 NLRP3 候选药物：现有和新兴技术的经验教训。
Screening NLRP3 drug candidates in clinical development: lessons from existing and emerging technologies.
发表日期：2024
作者：
Isak W Tengesdal, Migachelle Banks, Charles A Dinarello, Carlo Marchetti
来源：
CYTOKINE & GROWTH FACTOR REVIEWS
摘要：
数十年的证据表明 IL-1β 是急性和慢性炎症性疾病的主要调节细胞因子。已批准的旨在抑制 IL-1 信号传导的生物制剂已显示出功效，但安全性参差不齐。最近，靶向 NLRP3 激活（IL-1β 的上游介质）引起了最多的关注。 NLRP3 异常激活已被证明参与了从神经生成疾病到心脏代谢综合征和癌症等多种病理状况的进展。旨在限制 NLRP3 功能的药理学和遗传学策略已被证明在许多临床前疾病模型中有效。这些证据导致人们在靶向 NLRP3 的口服活性小分子的产生和临床测试方面付出了巨大的努力。在本报告中，我们讨论了这些具有转化潜力的分子的不同特性，并描述了目前可用于筛选 NLRP3 靶向分子的技术，强调了每种方法的优点和局限性。版权所有 © 2024 Tengesdal、Banks、Dinarello 和 Marchetti。
Decades of evidence positioned IL-1β as a master regulatory cytokine in acute and chronic inflammatory diseases. Approved biologics aimed at inhibiting IL-1 signaling have shown efficacy but variable safety. More recently, targeting NLRP3 activation, an upstream mediator of IL-1β, has garnered the most attention. Aberrant NLRP3 activation has been demonstrated to participate in the progression of several pathological conditions from neurogenerative diseases to cardio-metabolic syndromes and cancer. Pharmacological and genetic strategies aimed to limit NLRP3 function have proven effective in many preclinical models of diseases. These evidences have lead to a significant effort in the generation and clinical testing of small orally active molecules that can target NLRP3. In this report, we discuss different properties of these molecules with translational potential and describe the technologies currently available to screen NLRP3 targeting molecules highlighting advantages and limitations of each method.Copyright © 2024 Tengesdal, Banks, Dinarello and Marchetti.