Identification of CDK4/6 Inhibitors as Small Molecule NLRP3 Inflammasome Activators that Facilitate IL-1β Secretion and T Cell Adjuvanticity,Journal of Medicinal Chemistry

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Identification of CDK4/6 Inhibitors as Small Molecule NLRP3 Inflammasome Activators that Facilitate IL-1β Secretion and T Cell Adjuvanticity
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-20 , DOI: 10.1021/acs.jmedchem.4c00516
Adam M Weiss _{1,

2} , Marcos A Lopez _{1,

2} , Matthew G Rosenberger ₁ , Jeremiah Y Kim ₁ , Jingjing Shen ₁ , Qing Chen ₁ , Trevor Ung ₁ , Udoka M Ibeh _{1,

3} , Hannah Riley Knight ₁ , Nakisha S Rutledge ₁ , Bradley Studnitzer _{1,

2} , Stuart J Rowan _{1,

2} , Aaron P Esser-Kahn ₁

Affiliation

Several FDA-approved adjuvants signal through the NLRP3 inflammasome and IL-1β release. Identifying small molecules that induce IL-1β release could allow targeted delivery and structure–function optimization, thereby improving safety and efficacy of next-generation adjuvants. In this work, we leverage our existing high throughput data set to identify small molecules that induce IL-1β release. We find that ribociclib induces IL-1β release when coadministered with a TLR4 agonist in an NLRP3- and caspase-dependent fashion. Ribociclib was formulated with a TLR4 agonist into liposomes, which were used as an adjuvant in an ovalbumin prophylactic vaccine model. The liposomes induced antigen-specific immunity in an IL-1 receptor-dependent fashion. Furthermore, the liposomes were coadministered with a tumor antigen and used in a therapeutic cancer vaccine, where they facilitated rejection of E.G7-OVA tumors. While further chemical optimization of the ribociclib scaffold is needed, this study provides proof-of-concept for its use as an IL-1 producing adjuvant in various immunotherapeutic contexts.

中文翻译：

将 CDK4/6 抑制剂鉴定为促进 IL-1β 分泌和 T 细胞佐剂的小分子 NLRP3 炎性体激活剂

FDA 批准的几种佐剂通过 NLRP3 炎性体和 IL-1β 释放发出信号。识别诱导 IL-1β 释放的小分子可以实现靶向递送和结构功能优化，从而提高下一代佐剂的安全性和有效性。在这项工作中，我们利用现有的高通量数据集来识别诱导 IL-1β 释放的小分子。我们发现，当 ribociclib 与 TLR4 激动剂以 NLRP3 和 caspase 依赖性方式共同给药时，会诱导 IL-1β 释放。 Ribociclib 与 TLR4 激动剂一起配制到脂质体中，在卵清蛋白预防性疫苗模型中用作佐剂。脂质体以 IL-1 受体依赖性方式诱导抗原特异性免疫。此外，脂质体与肿瘤抗原共同施用并用于治疗性癌症疫苗，它们促进了 E.G7-OVA 肿瘤的排斥。虽然需要对 ribociclib 支架进行进一步的化学优化，但这项研究为其在各种免疫治疗背景下用作产生 IL-1 的佐剂提供了概念验证。

更新日期：2024-08-20

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