OICR-9429 is an effective and highly potent inhibitor of the WD repeat domain 5 (WDR5) with a Kd value of 93 ± 28nM [1]. WDR5 is a common scaffold protein that typically forms a nucleosome-modifying protein complex with histones. OICR-9429 binds competitively to the central peptide binding pocket of WDR5, blocking the interaction between WDR5 and the mixed-lineage leukemia (MLL) protein [2-3]. OICR-9429 can be used in the research of various cancers such as non-MLL rearrangement leukemia, colon cancer, pancreatic cancer, prostate cancer, and bladder cancer [4].
In vitro, OICR-9429 (0-400μM; 48h) inhibited the cell proliferation and metastasis of bladder cancer cell lines (T24, UM-UC-3, and TCCSUP) in a dose-dependent manner, promoted the level of cell apoptosis, and reduced the H3K4me3 level in the cells [5]. OICR-9429 (75 and 100μM; 48h) treatment significantly reduced the viability and colony formation ability of PCa cells in a dose-dependent manner, and induced G0/G1 phase arrest [6].
In vivo, OICR-9429 (30 and 60mg/kg/day; every 2 days for 16 days; i.p.) treatment significantly inhibited the tumor growth of bladder cancer cell (BCa) xenograft mice, enhanced chemosensitivity, and reduced the toxicity of cisplatin in BCa [5]. OICR-9429 (1mg/kg/day; i.p.) treatment reduced the peritoneal cell density and the thickness of the interstitial dense zone in mice with peritoneal fibrosis induced by methylglyoxal (MGO), decreased the number of H3K4me3 positive cells, and alleviated the peritoneal fibrosis and inflammation in mice [7].
References:
[1] Grebien F, Vedadi M, Getlik M, et al. Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia. Nat Chem Biol. 2015;11(8):571-578.
[2] Migliori, V., Mapelli, M., and Guccione, E. On WD40 proteins: Propelling our knowledge of transcriptional control Epigenetics 7(8), 815-822 (2012).
[3] Guccione, E., Bassi, C., Casadio, F., et al. Methylation of histone H3R2 by PRMT6 and H3K4 by an MLL complex are mutually exclusive. Nature 449, 933-937 (2007).
[4] Gurung R, Om D, Pun R, et al. Recent Progress in Modulation of WD40-Repeat Domain 5 Protein (WDR5): Inhibitors and Degraders. Cancers 2023, 15, 3910[EB/OL].(2023)
[5] Zhang J, Zhou Q, Xie K, et al. Targeting WD repeat domain 5 enhances chemosensitivity and inhibits proliferation and programmed death-ligand 1 expression in bladder cancer. J Exp Clin Cancer Res. 2021;40(1):203. Published 2021 Jun 21.
[6] Zhou Q, Chen X, He H, et al. WD repeat domain 5 promotes chemoresistance and Programmed Death-Ligand 1 expression in prostate cancer[J]. Theranostics, 2021, 11(10): 4809.
[7] Hara D, Sasaki K, Doi S, et al. Targeting MLL1/WDR5‐Mediated Epigenetic Regulation Mitigates Peritoneal Fibrosis by Reducing p16INK4a[J]. The FASEB Journal, 2025, 39(8): e70543.
OICR-9429是一种有效的高亲和力的WD repeat domain 5（WDR5）抑制剂，与WDR5结合的Kd值为93±28nM [1]。WDR5是一种常见的支架蛋白，通常与组蛋白形成核小体修饰蛋白复合物。OICR-9429通过与WDR5的中心肽结合口袋结合，竞争性地阻断WDR5与混合谱系白血病（MLL）蛋白的相互作用 [2-3]。OICR-9429可用于非MLL重排白血病、结肠癌、胰腺癌、前列腺癌、膀胱癌等多种癌症的研究 [4]。
在体外，OICR-9429（0-400μM; 48h）以剂量依赖性方式抑制了膀胱癌细胞系（T24、UM-UC-3和TCCSUP）的细胞增殖和转移，促进了细胞凋亡水平并降低了细胞中的H3K4me3水平 [5]。OICR-9429（75和100μM; 48h）处理以剂量依赖性方式显著降低了PCa细胞的活力和集落形成能力，并诱导G0/G1相停滞 [6]。
在体内，OICR-9429（30和60mg/kg/day; every 2 days for 16 days; i.p.）治疗显著抑制了膀胱癌细胞（BCa）异种移植小鼠的肿瘤生长，增强化学敏感性并降低顺铂在BCa中的毒性 [5]。OICR-9429（1mg/kg/day; i.p.）治疗降低了甲基乙二醛（MGO）诱导的腹膜纤维化小鼠的腹膜细胞密度和间皮下致密区厚度，减少了H3K4me3阳性细胞的数量，减轻了小鼠的腹膜纤维化和炎症 [7]。