Selective Inhibition of Lysine‐Specific Demethylase 5A (KDM5A) Using a Rhodium(III) Complex for Triple‐Negative Breast Cancer Therapy

Abstract

Lysine-specific demethylase 5A (KDM5A) has recently become a promising target for epigenetic therapy. In this study, we designed and synthesized metal complexes bearing ligands with reported demethylase and p27 modulating activities. The Rh(III) complex 1 was identified as a direct, selective and potent inhibitor of KDM5A that directly abrogate KDM5A demethylase activity via antagonizing the KDM5A-tri-/di-methylated histone 3 protein-protein interaction (PPI) in vitro and in cellulo. Complex 1 induced accumulation of H3K4me3 and H3K4me2 levels in cells, causing growth arrest at G1 phase in the triple-negative breast cancer (TNBC) cell lines, MDA-MB-231 and 4T1. Finally, 1 exhibited potent anti-tumor activity against TNBC xenografts in an in vivo mouse model, presumably via targeting of KDM5A and hence upregulating p27. Moreover, complex 1 was less toxic compared with two clinical drugs, cisplatin and doxorubicin. To our knowledge, complex 1 is the first metal-based KDM5A inhibitor reported in the literature. We anticipate that complex 1 may be used as a novel scaffold for the further development of more potent epigenetic agents against cancers, including TNBC.

Pharmacological Inhibition of LSD1 for Cancer Treatment

“…In addition, metal-based complexes may be another choice for achieving potent and selective LSD1 inhibitors. Metal complexes are characterized by their stability, distinct geometries, and diverse structures, making them suitable as chemical scaffolds for exploring the binding sites of proteins [133,140,141,142,143,144]. For example, our group has identified a rhodium(III)-based inhibitor with potency and selectivity for LSD1 in vitro and in cellulo [133].…”

Porphyrin MOF Dots–Based, Function‐Adaptive Nanoplatform for Enhanced Penetration and Photodynamic Eradication of Bacterial Biofilms

“…Smaller nanoparticles have been reported to have better biofilm penetration . Recently, several targeted drug candidates were designed for antibacterial and cancer therapy to improve therapeutic efficiency . Hence, we hypothesize that the ultrasmall‐sized and positively charged pMOF dots could possess outstanding photodynamic efficacy, excellent biofilm penetration, and bacterial targeting ability compared with bulk pMOFs.…”

The design and development of covalent protein-protein interaction inhibitors for cancer treatment

“…Proteins occupy almost half of the dry mass of a cell, and the disruption of PPIs often causes diseases, including cancer [9,10]. Hence, research on PPI plays a central role in progressing our understanding of molecular biology and human diseases, as well as for developing new therapeutic agents in drug discovery [6,11,12].…”