Structural Simplification of OG-001: Phenyl-to-methyl Substitution Improves Selectivity for Tumor-associated hCA IX and hCA XII

Uzunalioğlu C., Demir Yazıcı K., Trawally M., Akdemir A., Supuran C. T., Güzel Akdemir Ö.

13th Conference on Carbonic Anhydrases (ICCA 2025), Sevilla, İspanya, 2 - 04 Nisan 2025, ss.69, (Özet Bildiri)

  • Yayın Türü: Bildiri / Özet Bildiri
  • Basıldığı Şehir: Sevilla
  • Basıldığı Ülke: İspanya
  • Sayfa Sayıları: ss.69
  • İstanbul Üniversitesi Adresli: Evet

Özet

hCA IX and hCA XII inhibitors have emerged as a promising area of research to develop 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. 1 Large hydrophobic molecules in lead optimization are frequently linked to low drug likeness, promiscuity, and high attrition rates in drug discovery and development. Structural simplification enhances the efficiency and success rate of drug design by reducing molecular weight and lipophilicity, enhancing pharmacokinetic profiles and selectivity, and reducing side effects. 2 In this study, we report the structural simplification and selectivity optimization of OG 001, a non-selective hCA IX and XII potent inhibitor. By replacing a phenyl group with a smaller methyl substituent, we aimed to reduce the promiscuity of OG-001 and enhance its target specificity. The modified compound demonstrated improved selectivity for hCA IX and XII while maintaining potent inhibitory activity.