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基于吡唑并[3,4 - ]嘧啶骨架的抗癌激酶抑制剂的最新进展。

Recent developments in anticancer kinase inhibitors based on the pyrazolo[3,4-]pyrimidine scaffold.

作者信息

Baillache Daniel J, Unciti-Broceta Asier

机构信息

Cancer Research UK Edinburgh Centre , Institute of Genetics and Molecular Medicine , University of Edinburgh , Crewe Road South , Edinburgh EH4 2XR , UK . Email:

出版信息

RSC Med Chem. 2020 Sep 8;11(10):1112-1135. doi: 10.1039/d0md00227e. eCollection 2020 Oct 1.

DOI:10.1039/d0md00227e
PMID:33479617
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7652001/
Abstract

Pyrazolo[3,4-]pyrimidines have become of significant interest for the medicinal chemistry community as a privileged scaffold for the development of kinase inhibitors to treat a range of diseases, including cancer. This fused nitrogen-containing heterocycle is an isostere of the adenine ring of ATP, allowing the molecules to mimic hinge region binding interactions in kinase active sites. Similarities in kinase ATP sites can be exploited to direct the activity and selectivity of pyrazolo[3,4-]pyrimidines to multiple oncogenic targets through focussed chemical modification. As a result, pharma and academic efforts have succeeded in progressing several pyrazolo[3,4-]pyrimidines to clinical trials, including the BTK inhibitor ibrutinib, which has been approved for the treatment of several B-cell cancers. In this review, we examine the pyrazolo[3,4-]pyrimidines currently in clinical trials for oncology patients, as well as those published in the literature during the last 5 years for different anticancer indications.

摘要

吡唑并[3,4 -]嘧啶作为开发激酶抑制剂以治疗包括癌症在内的一系列疾病的优势骨架，已引起药物化学界的极大关注。这种稠合含氮杂环是ATP腺嘌呤环的电子等排体，使分子能够模拟激酶活性位点中的铰链区结合相互作用。激酶ATP位点的相似性可通过聚焦化学修饰来利用，以引导吡唑并[3,4 -]嘧啶对多个致癌靶点的活性和选择性。因此，制药公司和学术界已成功将几种吡唑并[3,4 -]嘧啶推进到临床试验阶段，包括已被批准用于治疗几种B细胞癌症的BTK抑制剂伊布替尼。在本综述中，我们研究了目前正在针对肿瘤患者进行临床试验的吡唑并[3,4 -]嘧啶，以及过去5年中针对不同抗癌适应症发表在文献中的那些化合物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e7b/7652001/820873b0463c/d0md00227e-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e7b/7652001/6003fba8e2a3/d0md00227e-f1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e7b/7652001/5abe369acefa/d0md00227e-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e7b/7652001/59f4922cccf8/d0md00227e-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e7b/7652001/07fd835da3ec/d0md00227e-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e7b/7652001/820873b0463c/d0md00227e-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e7b/7652001/6003fba8e2a3/d0md00227e-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e7b/7652001/fa5b7b09f73a/d0md00227e-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e7b/7652001/5abe369acefa/d0md00227e-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e7b/7652001/59f4922cccf8/d0md00227e-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e7b/7652001/07fd835da3ec/d0md00227e-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e7b/7652001/820873b0463c/d0md00227e-f6.jpg

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