期刊
CHEMBIOCHEM
卷 22, 期 18, 页码 2741-2761出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.202100121
关键词
carbonic anhydrase; carborane; cobalt bis(dicarbollide); crystallography; enzyme inhibition; SAR studies
资金
- Czech Science Foundation [18-27648S]
- Technology Agency of the Czech Republic [TE01020028]
- Ministry of Education of the Czech Republic [CZ.02.1.01/0.0/0.0/16_019/0000868, EATRIS-CZ LM2015064]
This review discusses the recent advancements in designing inhibitors of human carbonic anhydrase IX (CA IX) using space-filling carborane and cobalt bis(dicarbollide) clusters. The inhibitors showed promising results in preclinical evaluation with low toxicity, favorable pharmacokinetics, and inhibition of tumor growth, making them potential candidates for drug development or combination therapy.
This review describes recent progress in the design and development of inhibitors of human carbonic anhydrase IX (CA IX) based on space-filling carborane and cobalt bis(dicarbollide) clusters. CA IX enzyme is known to play a crucial role in cancer cell proliferation and metastases. The new class of potent and selective CA IX inhibitors combines the structural motif of a bulky inorganic cluster with an alkylsulfamido or alkylsulfonamido anchor group for Zn2+ ion in the enzyme active site. Detailed structure-activity relationship (SAR) studies of a large series containing 50 compounds uncovered structural features of the cluster-containing inhibitors that are important for efficient and selective inhibition of CA IX activity. Preclinical evaluation of selected compounds revealed low toxicity, favorable pharmacokinetics and ability to reduce tumor growth. Cluster-containing inhibitors of CA IX can thus be considered as promising candidates for drug development and/or for combination therapy in boron neutron capture therapy (BNCT).
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