Aurora kinases, especially AURKA, are critical for mitotic regulation, and their dysregulation is linked to tumorigenesis, making AURKA a promising anticancer target. Conventional ATP-competitive AURKA inhibitors suffer from low subtype selectivity and failure to disrupt noncatalytic functions, resulting in limited therapeutic efficacy and substantial toxic side effects. Proteolysis-targeting chimera (PROTAC) technology presents a promising alternative by enabling degradation of the target protein, thereby blocking both catalytic and noncatalytic functions. Here, we developed AURKA degraders based on the allosteric inhibitor CAM2602 and CRBN-recruiting moieties. Compound CT3 was characterized as a potent and subtype-selective AURKA degrader. It displayed enhanced antiproliferative activity compared with the parental inhibitor in Jurkat cells, which have high CRBN and AURKA expression, and demonstrated effective in vivo antitumor effects in Jurkat xenograft models. Further structural optimization is expected to generate promising AURKA degrader candidates for drug development.
Yuanna Ye, Yalan Feng, Hao Wang et al.· Journal of Medicinal Chemist...· 0 citations
Triple-negative breast cancer (TNBC) represents a highly aggressive breast cancer subtype characterized by a paucity of effective therapeutic options. Consequently, the development of targeted therapies constitutes a promising strategy for TNBC treatment. It has been demonstrated that combining CDK12 and PARP1 inhibitors can trigger synthetic lethality in TNBC cells. In the present study, employing a pharmacophore fusion strategy, we designed and synthesized a series of dual-target inhibitors against CDK12 and PARP1. Among them, compound 20b exerted potent inhibition activity against both CDK12 and PARP1 at nanomolar concentrations. It exhibited markedly superior antiproliferative effects compared with single-target inhibitors and effectively reduced pSer2-CTD (Ser2 phosphorylation) and PAR levels in TNBC cells. Furthermore, compound 20b produced robust colony formation inhibitory effects in TNBC cell lines, accompanied by cell cycle arrest and apoptosis induction. The dual-target CDK12/PARP1 inhibitor 20b developed herein represents a novel lead molecule for TNBC drug development.
Z. Zhong, Miao Sun, Zhiwen Luo et al.· European journal of medicina...· 0 citations
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