
設計了一種新型的前藥化合物,可轉化為活性形式,共價修飾活性位點的特定組氨酸殘基,這是一項艱難的任務,並應用於膜蛋白碳酸酐酶IX,該蛋白在缺氧實體瘤中高度過表達,對癌細胞的生存和增殖很重要,因為它可以使腫瘤微環境酸化,從而有助於侵襲和轉移過程。


coremsg

We designed novel pre-drug compounds that transform into an active form that covalently modifies particular His residue in the active site, a difficult task to achieve, and applied to carbonic anhydrase (CAIX), a transmembrane protein, highly overexpressed in hypoxic solid tumors, important for cancer cell survival and proliferation because it acidifies tumor microenvironment helping invasion and metastases processes. The designed compounds have several functionalities: 1) primary sulfonamide group recognizing carbonic anhydrases (CA), 2) high-affinity moieties specifically recognizing CAIX among all CA isozymes, and 3) forming a covalent bond with the His64 residue. Such targeted covalent compounds possess both high initial affinity and selectivity for the disease target protein followed by complete irreversible inactivation of the protein via covalent modification. Our designed prodrug candidates bearing moderately active pre-vinyl sulfone esters or weakly active carbamates optimized for mild covalent modification activity to avoid toxic non-specific modifications and selectively target CAIX. The lead inhibitors reached 2 pM affinity, highest among known CAIX inhibitors. The strategy could be used for any disease drug target protein bearing a His residue in the vicinity of the active site.

### Competing Interest Statement

The authors declare that they have patent applications and patents on carbonic anhydrase inhibitors.

Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX

針對癌症的預-乙烯基磺酸酯共價抑制劑標靶碳酸酐酶ix


針對癌症的預-乙烯基磺酸酯共價抑制劑標靶碳酸酐酶IX
