BCI-121 is a competitive inhibitor of SMYD3, which impairs SMYD3-mediated histone H4 methylation [1]. BCI-121 competes with histones for binding to SMYD3 and reduces SMYD3 binding to the promoter region of the target genes as well as the expression of downstream effectors ITGB6 and ITGAM[2]. BCI-121 has been widely used to inhibit the proliferation of ovarian cancer cells and the epithelial-mesenchymal transition of breast cancer[3].
In vitro, BCI-121 treatment for 5 days significantly inhibited the proliferation of D458 cells with an IC50 value of 80μM, and led to the downregulation of pRBSer795 and the upregulation of RB protein[4]. Treatment with 100μM BCI-121 for 72 hours significantly inhibited the viability of A549 cells and H1650 cells, and decreased the levels of H3K4me3 and the transcriptional level of ANO1[5]. Treatment with 100μM BCI-121 for 4 days significantly reduced the levels of H4K20me3 and p-Akt (S473) in HGC-27 and SGC-7901 cells, and increased the level of EMP1 protein[6].
In vivo, BCI-121 treatment via daily intraperitoneal injections (1mg/kg) for three consecutive days could reverse the elevated H3K4me3 levels in the tauopathy mouse models, improve the cognitive deficits of the mice and restore the function and expression of neuronal synaptic NMDAR[7]. Three consecutive days of daily intraperitoneal injection of BCI-121 (20mg/kg) exacerbated the renal tubular cell injury and apoptosis induced by ischemia-reperfusion (IR) in mice, resulting in severe renal dysfunction and pathological changes[8].
References:
[1] Peserico A, Germani A, Sanese P, et al. A SMYD3 small‐molecule inhibitor impairing cancer cell growth[J]. Journal of cellular physiology, 2015, 230(10): 2447-2460.
[2] Lyu T, Jiang Y, Jia N, et al. SMYD3 promotes implant metastasis of ovarian cancer via H3K4 trimethylation of integrin promoters[J]. International journal of cancer, 2020, 146(6): 1553-1567.
[3] Rubio-Tomás T. Novel insights into SMYD2 and SMYD3 inhibitors: from potential anti-tumoural therapy to a variety of new applications[J]. Molecular biology reports, 2021, 48(11): 7499-7508.
[4] Asuthkar S, Venkataraman S, Avilala J, et al. SMYD3 promotes cell cycle progression by inducing cyclin D3 transcription and stabilizing the cyclin D1 protein in medulloblastoma[J]. Cancers, 2022, 14(7): 1673.
[5] Zhong D, Zhan Z, Zhang J, et al. SMYD3 regulates the abnormal proliferation of non-small-cell lung cancer cells via the H3K4me3/ANO1 axis: Dian Zhong et al[J]. Journal of biosciences, 2022, 47(3): 53.
[6] Zeng Y, Ma G, Cai F, et al. SMYD3 drives the proliferation in gastric cancer cells via reducing EMP1 expression in an H4K20me3-dependent manner[J]. Cell death & disease, 2023, 14(6): 386.
[7] Williams J B, Cao Q, Wang W, et al. Inhibition of histone methyltransferase Smyd3 rescues NMDAR and cognitive deficits in a tauopathy mouse model[J]. Nature Communications, 2023, 14(1): 91.
[8] Du X, Shen F, Yu C, et al. SMYD3 as an epigenetic regulator of renal tubular cell survival and regeneration following acute kidney injury in mice[J]. The FASEB Journal, 2025, 39(9): e70533.