Seminar: Carbonic Anhydrases - Evergreen Drug Targets (Prof. Claudiu T. Supuran)

Thursday, 20 February 2020 - 12:00pm – Thursday, 20 February 2020 - 1:00pm  |  ChemSci M11

Abstract

 

Carbonic anhydrases (CA, EC 4.2.1.1), are involved in many physiologic/pathologic processes connected to pH regulation, metabolism, secretion of electrolytes, diuresis, tumorigenesis (invasion and dissemination of the tumor), neuropathic pain and arthritis. Several CA inhibitors (CAIs) classes that selectively inhibit the 12 catalytically active human isoforms were unraveled in the last decade together with a general procedure for obtaining them (the tail approach). They belong to sulfonamides and isosteres, dithiocarbamates and related compounds, carboxylates and hydroxamates, coumarins, sulfocoumarin, benzoxaboroles, selenols, etc. In hyoxic tumors, alone or in combination with other agents, inhibitors targeting CA IX/XII inhibit the growth of primary tumors, the formation of metastases and deplete the cancer stem cell population, making them unique among all anticancer drugs available to date. SLC-0111, a sulfonamide CAI discovered by the author, successfully finished a Phase I clinical trial for the treatment of advanced, metastatic solid tumors in 2016. This compound is now in Phase II clinical trials, alone or in combination with other agents such as gemcitabine. 1-6 Other recent applications of CAIs and CA activators will be also discussed.7-10 

1. Supuran CT. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nature Rev Drug Discov 2008; 7: 168-81. 

2. Neri D, Supuran CT. Interfering with pH regulation in tumours as a therapeutic strategy. Nature Rev Drug Discov 2011; 10: 767-77. 

3. Supuran CT. Structure and function of carbonic anhydrases. Biochem J. 2016; 473: 2023-32. 

4. Supuran CT, Alterio V, Di Fiore A, et al. Inhibition of carbonic anhydrase IX targets primary tumors, metastases, and cancer stem cells: Three for the price of one. Med Res Rev. 2018; 38: 1799-1836. 

5. Supuran CT. Carbonic anhydrase inhibitors as emerging agents for the treatment and imaging of hypoxic tumors. Expert Opin Investig Drugs. 2018 ;27(12):963-970 

6. https://clinicaltrials.gov/ct2/show/NCT03450018 (last updated on March 1, 2018). 

7. Supuran CT. The management of glaucoma and macular degeneration. Expert Opin Ther Pat. 2019;29:745-747. 

8. Nocentini A, Supuran CT. Advances in the structural annotation of human carbonic anhydrases and impact on future drug discovery. Expert Opin Drug Discov. 2019; 14: 1175-1197. 

9. Supuran CT. How many carbonic anhydrase inhibition mechanisms exist? J Enzyme Inhib Med Chem. 2016;31:345-360. 

10. Supuran CT. Carbonic anhydrase activators. Future Med Chem. 2018; 10: 561-573.