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Necroptosis is a form of regulated necrosis controlled by receptor-interacting kinase 1 (RIPK1 or RIP1), RIPK3 (RIP3), and pseudokinase mixed lineage kinase domain-like protein (MLKL). Increasing evidence suggests that necroptosis is closely associated with pathologies including inflammatory diseases, neurodegenerative diseases, and cancer metastasis. Herein, we discovered the small-molecule PK6 and its derivatives as a novel class of necroptosis inhibitors that directly block the kinase activity of RIPK1. Optimization of PK6 led to PK68, which has improved efficacy for the inhibition of RIPK1-dependent necroptosis, with an EC 50 of around 14–22 nM in human and mouse cells. PK68 efficiently blocks cellular activation of RIPK1, RIPK3, and MLKL upon necroptosis stimuli. PK68 displays reasonable selectivity for inhibition of RIPK1 kinase activity and favorable pharmacokinetic properties. Importantly, PK68 provides strong protection against TNF-α-induced systemic inflammatory response syndrome in vivo. Moreover, pre-treatment of PK68 significantly represses metastasis of both melanoma cells and lung carcinoma cells in mice. Together, our study demonstrates that PK68 is a potent and selective inhibitor of RIPK1 and also highlights its great potential for use in the treatment of inflammatory disorders and cancer metastasis.

Breast cancer is a multistep, multifactorial, and heterogeneous disease. Significant transformations have occurred in the systemic management of breast cancer in the past decade. Due to the further understanding of pathogenesis, scientists have found plenty of signaling pathways and correspondingly therapeutic targets in breast cancer, such as hormone receptor, human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), phosphoinositide-3-kinase (PI3K), v-akt murine thymoma viral oncogene homolog (AKT), mechanistic target of rapamycin (mTOR), cyclin-dependent kinase 4/6 (CDK4/6), poly (adenosine diphosphate-ribose) polymerase (PARP), and programmed death-1 (PD-1). Targeted therapy, which optimizes the accuracy of antitumor activity and minimizes toxicity to normal tissues, plays a crucial role in breast cancer treatment in the era of precision medicine. In this review, we aimed to summarize the latest developments in targeted therapy for breast cancer and discuss the existing problems.

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