Targeting hypoxic tumor cell viability with carbohydrate-based carbonic anhydrase IX and XII inhibitors.
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Morris JC, Chiche J, Grellier C, Lopez M, Bornaghi LF, Maresca A, Supuran CT, Pouyssegur J, Poulsen SA
Targeting hypoxic tumor cell viability with carbohydrate-based carbonic anhydrase IX and XII inhibitors.
J Med Chem. 2011 Oct 13;54(19):6905-18. doi: 10.1021/jm200892s. Epub 2011 Sep 2.
- PubMed ID
- 21851094 [ View in PubMed]
- Abstract
Carbonic anhydrase (CA) enzymes, specifically membrane-bound isozymes CA IX and CA XII, underpin a pH-regulating system that enables hypoxic tumor cell survival and proliferation. CA IX and XII are implicated as potential targets for the development of new hypoxic cancer therapies. To date, only a few small molecules have been characterized in CA-relevant cell and animal model systems. In this paper, we describe the development of a new class of carbohydrate-based small molecule CA inhibitors, many of which inhibit CA IX and XII within a narrow range of low nanomolar K(i) values (5.3-11.2 nM). We evaluate for the first time carbohydrate-based CA inhibitors in cell-based models that emulate the protective role of CA IX in an acidic tumor microenvironment. Our findings identified two inhibitors (compounds 5 and 17) that block CA IX-induced survival and have potential for development as in vivo cancer cell selective inhibitors.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Acetazolamide Carbonic anhydrase 1 Ki (nM) 250 N/A N/A Details Acetazolamide Carbonic anhydrase 12 Ki (nM) 5.7 N/A N/A Details Acetazolamide Carbonic anhydrase 2 Ki (nM) 12 N/A N/A Details - Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Oxygen Approved Vet Approved CA12 771 upregulated Oxygen deficiency results in increased expression of CA12 mRNA 15q22.2 Oxygen Approved Vet Approved CA9 768 upregulated Oxygen deficiency results in increased expression of CA9 mRNA 9p13.3