2. Academic Validation
  3. Isoxazole-pyrimidine derivatives as TACC3 inhibitors: A novel modality to targeted cancer therapy

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

  • Bioorg Chem. 2025 Mar:156:108204. doi: 10.1016/j.bioorg.2025.108204.
Deniz Lengerli 1,  Özge Akbulut Çalışkan 2,  Kübra Çalışkan 1,  Özge Saatci 2,  Chaemin Lim 3,  Sridhar Vempati 3,  Burcu Çalışkan 1,  Özgür Şahin 2,  Erden Banoglu 4
Affiliations

Affiliations

  • 1 Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06560 Ankara, Turkey.
  • 2 Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC 29208, USA.
  • 3 A2A Pharmaceuticals, Inc., 1185 Avenue of the Americas, New York, NY 10036, USA.
  • 4 Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06560 Ankara, Turkey. Electronic address: banoglu@gazi.edu.tr.
PMID: 39889548 DOI: 10.1016/j.bioorg.2025.108204
Abstract

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.

Keywords

Anticancer agent; Breast cancer; Isoxazole; Pyrimidine; TACC3.

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