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

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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.