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鉴定新型吡咯并嘧啶和吡咯并吡啶衍生物为有效的 ENPP1 抑制剂。

Identification of novel pyrrolopyrimidine and pyrrolopyridine derivatives as potent ENPP1 inhibitors.

机构信息

Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea.

Department of Chemistry, Korea University, Seoul, Republic of Korea.

出版信息

J Enzyme Inhib Med Chem. 2022 Dec;37(1):2434-2451. doi: 10.1080/14756366.2022.2119566.

DOI:10.1080/14756366.2022.2119566
PMID:36069240
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9467556/
Abstract

In an effort to discover novel scaffolds of non-nucleotide-derived Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibitors to stimulate the Stimulator of Interferon Genes (STING) pathway, we designed and synthesised pyrrolopyrimidine and pyrrolopyridine derivatives and performed structure-activity relationship (SAR) study. We found possessed high potency (IC = 25.0 nM) against ENPP1, and activated STING pathway in a concentration dependent manner. Also, in response to STING pathway activation, cytokines such as IFN- and IP-10 were induced by in a concentration dependent manner. Finally, we discovered that causes inhibition of tumour growth in 4T1 syngeneic mouse model. This study provides new insight into the designing of novel ENPP1 inhibitors and warrants further development of small molecule immune modulators for cancer immunotherapy.

摘要

为了发现新型非核苷酸衍生的外核苷酸焦磷酸酶/磷酸二酯酶 1（ENPP1）抑制剂支架以刺激干扰素基因刺激物（STING）途径，我们设计并合成了吡咯并嘧啶和吡咯吡啶衍生物，并进行了结构-活性关系（SAR）研究。我们发现化合物 对 ENPP1 具有高活性（IC = 25.0 nM），并以浓度依赖的方式激活 STING 途径。此外，在 STING 途径激活后，IFN- 和 IP-10 等细胞因子也被 以浓度依赖的方式诱导产生。最后，我们发现 可抑制 4T1 同基因小鼠模型中的肿瘤生长。本研究为新型 ENPP1 抑制剂的设计提供了新的见解，并为癌症免疫治疗的小分子免疫调节剂的进一步开发提供了依据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824a/9467556/4941e8d2742b/IENZ_A_2119566_F0007_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824a/9467556/4776f8bb59ed/IENZ_A_2119566_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824a/9467556/f434d76cad3c/IENZ_A_2119566_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824a/9467556/49bdebb7dfe3/IENZ_A_2119566_SCH0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824a/9467556/aaa1be87a171/IENZ_A_2119566_SCH0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824a/9467556/3c7b5322a1ab/IENZ_A_2119566_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824a/9467556/cd319eec313d/IENZ_A_2119566_F0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824a/9467556/67b7bb7268fb/IENZ_A_2119566_F0004_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824a/9467556/f3b952c37d38/IENZ_A_2119566_F0005_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824a/9467556/201a1a47f810/IENZ_A_2119566_F0006_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824a/9467556/4941e8d2742b/IENZ_A_2119566_F0007_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824a/9467556/4776f8bb59ed/IENZ_A_2119566_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824a/9467556/f434d76cad3c/IENZ_A_2119566_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824a/9467556/49bdebb7dfe3/IENZ_A_2119566_SCH0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824a/9467556/aaa1be87a171/IENZ_A_2119566_SCH0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824a/9467556/3c7b5322a1ab/IENZ_A_2119566_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824a/9467556/cd319eec313d/IENZ_A_2119566_F0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824a/9467556/67b7bb7268fb/IENZ_A_2119566_F0004_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824a/9467556/f3b952c37d38/IENZ_A_2119566_F0005_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824a/9467556/201a1a47f810/IENZ_A_2119566_F0006_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/824a/9467556/4941e8d2742b/IENZ_A_2119566_F0007_C.jpg

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