A Mitochondria-Targeted Phenylbutyric Acid Prodrug Confers Drastically Improved Anticancer Activities

J Med Chem. 2022 Jul 28;65(14):9955-9973. doi: 10.1021/acs.jmedchem.2c00640.

Ding Huang ¹, Qingwang Liu ², Maojie Zhang ¹, Yizhen Guo ³, Zhiying Cui ¹, Tao Li ¹, Dong Luo ¹, Biao Xu ⁴, Chao Huang ¹, Jian Guo ¹, Kin Yip Tam ³, Min Zhang ¹, Shao-Lin Zhang ¹, Yun He ¹

Affiliations

1 School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing 401331, P. R. China.
2 Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, P. R. China.
3 Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR 999078, P. R. China.
4 Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Department of Medicinal Chemistry, School of Pharmacy, Chongqing Medical University, Chongqing 400016, P. R. China.

PMID: 35818137 DOI: 10.1021/acs.jmedchem.2c00640

Abstract

Phenylbutyric acid (PBA) has been reported as a dual inhibitor of pyruvate dehydrogenase kinases (PDKs) and histone deacetylases (HDACs), exhibiting Anticancer effects. However, the low membrane permeability and poor cellular uptake limit its access to the target organelle, resulting in weak potencies against the intended targets. Herein, we report the design and identification of a novel 4-CF₃-phenyl triphenylphosphonium-based PBA conjugate (53) with improved in vitro and in vivo Anticancer activities. Compound 53 exhibited an IC₅₀ value of 2.22 μM against A375 cells, outperforming the parent drug PBA by about 4000-fold. In the A375 cell-derived xenograft mouse model, 53 reduced the tumor growth by 76% at a dose of 40 mg/kg, while PBA only reduced the tumor growth by 10% at a dose of 80 mg/kg. On the basis of these results, 53 may be considered for further preclinical evaluations for Cancer therapy.

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