Tail Elongation of OG-001 Enhances Selectivity Toward Tumor-Associated hCA IX and XII

Trawally M., Demir Yazıcı K., Güzel Akdemir Ö.

XII BrazMedChem 2025, Rio De Janeiro, Brezilya, 20 - 24 Eylül 2025, ss.1, (Tam Metin Bildiri)

  • Yayın Türü: Bildiri / Tam Metin Bildiri
  • Basıldığı Şehir: Rio De Janeiro
  • Basıldığı Ülke: Brezilya
  • Sayfa Sayıları: ss.1
  • İstanbul Üniversitesi Adresli: Evet

Özet

Human carbonic anhydrase IX (hCA IX) and XII (hCA XII), also known as the tumor-associated CA, are (over)expressed in various cancer types, causing hypoxia-induced acidosis, metastasis, and chemoresistance, resulting in tumor progression. Consequently, they emerged as attractive biological targets for cancer therapy, leading to the discovery of many small potential molecules, including our previously synthesized 5-sulfamoylindole-based OG-0011 (2-(hydrazinecarbonyl)-3-phenyl-1H-indole-5-sulfonamide) and SLC-0111 developed by Supuran et al.2, and has entered phase Ib/II clinical trials.3 Therefore, hCA IX and hCA XII inhibitors have emerged as a promising research area for developing more effective cancer treatments that can combat acidosis and reduce the insensitivity of cancer cells to chemotherapy and radiotherapy. However, achieving selectivity over off-target isoforms, hCA I and II, remains a significant challenge.4

The most effective strategy for achieving isoform selectivity among hCAs is the "tail approach", which involves elongating a molecule with either a hydrophilic or hydrophobic group via various linkers. While the zinc-binding sulfonamide and the aromatic ring-attached anchors the inhibitor within the conserved catalytic site, the appended tail allows the molecule to interact with variable residues in the external and middle-external rims of the active site, which differ among isoforms.5 One of the key differences in the external and middle-external rims is the bulky Phe131 residue in hCA II, which limits space and restricts access for larger substituents, whereas in hCA IX and XII, this residue is replaced by smaller amino acids (Val or Ala), creating a more open binding pocket (Figure 1).6

In this study, we report on the tail elongation and selectivity optimization of OG-001, a non-selective hCA IX and XII potent inhibitor, by adding benzenesulfonyl groups to the hydrazide part (Figure 2), obtaining SC derivatives, which are generally more selective for the tumor-associated hCA IX/XII over the off-targets cytosolic hCA I/II.