Isoxazole-pyrimidine derivatives as TACC3 inhibitors: A novel modality to targeted cancer therapy

LENGERLİ D., Çalışkan Ö. A., ÇALIŞKAN K., Saatci Ö., Lim C., Vempati S., ...Daha Fazla

Bioorganic Chemistry, cilt.156, 2025 (SCI-Expanded) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 156
  • Basım Tarihi: 2025
  • Doi Numarası: 10.1016/j.bioorg.2025.108204
  • Dergi Adı: Bioorganic Chemistry
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, Chimica, EMBASE, Veterinary Science Database
  • Anahtar Kelimeler: Anticancer agent, Breast cancer, Isoxazole, Pyrimidine, TACC3
  • Gazi Üniversitesi Adresli: Evet

Özet

Inhibiting the function of transforming acidic coiled-coil 3 (TACC3) offers a promising therapeutic approach for various cancers, such as breast, ovarian, and lung cancers. Our previous work introduced BO-264 as a novel chemotype for inhibiting TACC3 function, though it exhibited relatively low metabolic stability. In this study, sixty-two compounds were designed and synthesized to modify the structure of BO-264 to improve its metabolic stability while maintaining its potency. The tractable SAR results obtained by these novel analogs indicated that appropriate substitutions on the left-end phenyl-isoxazole and right-end morpholine groups improved metabolic stability while preserving potency. Among these, compound 13b exhibited approximately sevenfold improvement in metabolic stability and bioavailability while maintaining strong potency and a favorable safety profile. 13b markedly increased the levels of p-Histone H3 (Ser10), cleaved PARP, and p-H2AX (Ser139), indicative of mitotic arrest, apoptosis, and DNA damage, respectively. In addition, the protein-drug binding assay, DARTS, identified TACC3 as a biologically significant target of 13b, positioning it as an advanced lead compound for further development of clinically relevant TACC3 inhibitors in cancers with elevated TACC3 expression.