Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX

Area of Science:

• Medicinal Chemistry
• Oncology
• Biochemistry

Background:

• Carbonic anhydrase IX (CAIX) is overexpressed in hypoxic solid tumors, promoting cancer cell survival and proliferation by acidifying the tumor microenvironment.
• CAIX facilitates tumor invasion and metastasis, making it a critical target for cancer therapy.

Purpose of the Study:

• To design and synthesize novel prodrugs that selectively and irreversibly inhibit CAIX.
• To develop targeted covalent inhibitors with high affinity and specificity for CAIX.

Main Methods:

• Design of prodrugs incorporating a primary sulfonamide for CA recognition, high-affinity moieties for CAIX specificity, and a covalent warhead.
• Synthesis of prodrug candidates with optimized mild covalent modification activity (pre-vinylsulfone esters, carbamates).
• Evaluation of inhibitor affinity and selectivity against CAIX and other carbonic anhydrase isozymes.

Main Results:

• The designed prodrugs covalently modify a specific histidine residue (His64) in the CAIX active site.
• Lead inhibitors demonstrated exceptionally high affinity for CAIX, reaching 2 pM, surpassing known CAIX inhibitors.
• The prodrugs achieved selective and irreversible inactivation of CAIX, minimizing off-target modifications.

Conclusions:

• The developed prodrug strategy enables targeted covalent inhibition of CAIX, offering a promising approach for cancer treatment.
• This novel strategy of designing targeted covalent inhibitors can be extended to other disease-associated proteins with accessible histidine residues in their active sites.