Targeting cancer via Golgi α-mannosidase II inhibition: How far have we come in developing effective inhibitors?

Dysregulation of glycosylation pathways has been well documented in several types of cancer, where it often participates in cancer development and progression, especially cancer metastasis. Hence, inhibition of glycosidases such as mannosidases can disrupt the biosynthesis of glycans on cell surface...

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Bibliographic Details
Published in:Carbohydrate research 2021-10, Vol.508, p.108395, Article 108395
Main Authors: Lee, Zheng Yang, Loo, Jason Siau Ee, Wibowo, Agustono, Mohammat, Mohd Fazli, Foo, Jhi Biau
Format: Article
Language:English
Subjects:
Alpha mannosidase
Cancer
Golgi Apparatus
Mannosidases
N-glycosylation
Swainsonine
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Summary:Dysregulation of glycosylation pathways has been well documented in several types of cancer, where it often participates in cancer development and progression, especially cancer metastasis. Hence, inhibition of glycosidases such as mannosidases can disrupt the biosynthesis of glycans on cell surface glycoproteins and modify their role in carcinogenesis and metastasis. Several reviews have delineated the role of N-glycosylation in cancer, but the data regarding effective inhibitors remains sparse. Golgi α-mannosidase has been an attractive therapeutic target for preventing the formation of ß1,6-branched complex type N-glycans. However, due to its high structural similarity to the broadly specific lysosomal α-mannosidase, undesired co-inhibition occurs and this leads to serious side effects that complicates its potential role as a therapeutic agent. Even though extensive efforts have been geared towards the discovery of effective inhibitors, no breakthrough has been achieved thus far which could allow for their use in clinical settings. Improving the specificity of current inhibitors towards Golgi α-mannosidase is requisite in progressing this class of compounds in cancer chemotherapy. In this review, we highlight a few potent and selective inhibitors discovered up to the present to guide researchers for rational design of further effective inhibitors to overcome the issue of specificity. [Display omitted] •Suppression of Golgi alpha-mannosidase modifies the pathogenesis role of cancer especially metastasis.•Addressing selectivity issue may overcome problems associated with clinical trial flops of many potential compounds.•Iminosugars like swainosnine are still the most promising one to develop selective inhibitors due to its nanomolar affinity.•Other approaches like multivalency and targeting allosteric site may aid in development of more effective inhibitors.
ISSN:0008-6215
1873-426X
1873-426X
DOI:10.1016/j.carres.2021.108395