UNC1999 is an orally active inhibitor of EZH2 (IC50=2nM) and EZH1 (IC50=45nM)[1-2]. UNC1999 can be used to investigate the mechanisms of EZH2 and EZH1 in gene expression regulation, cancer development, and stem cell maintenance[3-4].
In vitro, treatment of human colorectal cancer cells (HCT116, LoVo, HCT-15, DLD-1) with UNC1999 (2.5–5μM) for 24–72 hours induces autophagy by upregulating LC3B gene expression transcriptionally, activates endoplasmic reticulum (ER) stress and the PERK/eIF2α pathway of the unfolded protein response (UPR), ultimately promoting tumor cell death[5]. UNC1999 (0.1–100μM) treatment of human bladder cancer cell lines E-J and 5637 for 24–120 hours, UNC1999 significantly inhibits cell proliferation and migration while inducing apoptosis by suppressing EZH2 activity and blocking the JAK2/STAT3 signaling pathway[6].
In vivo, intraperitoneal injection of UNC1999 (15–25mg/kg) twice weekly for 3 weeks in NOG mice bearing MM.1S human multiple myeloma xenografts significantly inhibits tumor growth and prolongs survival[7]. Intraperitoneal injection of UNC1999 (25mg/kg) twice weekly for 4 weeks in BALB/c nude mice inoculated with Y79 human retinoblastoma cells significantly suppresses the growth of subcutaneous xenograft tumors[8].
References:
[1] Zhou C, He A, Kang Q, et al. Development of a UPLC-MS/MS method for determination of a dual EZH1/2 inhibitor UNC1999 in rat plasma. Bioanalysis. 2022 Jan;14(2):67-74.
[2] Xu B, On DM, Ma A, et al. Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia. Blood. 2015 Jan 8;125(2):346-57.
[3] Shinno Y, Takenobu H, Sugino RP, et al. Polycomb EZH1 regulates cell cycle/5-fluorouracil sensitivity of neuroblastoma cells in concert with MYCN. Cancer Sci. 2022 Dec;113(12):4193-4206.
[4] Zhang Q, Deng X, Tang X, et al. MicroRNA-20a Suppresses Tumor Proliferation and Metastasis in Hepatocellular Carcinoma by Directly Targeting EZH1. Front Oncol. 2021 Dec 16;11:737986.
[5] Hsieh YY, Lo HL, Yang PM. EZH2 inhibitors transcriptionally upregulate cytotoxic autophagy and cytoprotective unfolded protein response in human colorectal cancer cells. Am J Cancer Res. 2016 Aug 1;6(8):1661-80.
[6] Chen Z, Du Y, Liu X, et al. EZH2 inhibition suppresses bladder cancer cell growth and metastasis via the JAK2/STAT3 signaling pathway. Oncol Lett. 2019 Jul;18(1):907-915.
[7] Rizq O, Mimura N, Oshima M, et al. Dual Inhibition of EZH2 and EZH1 Sensitizes PRC2-Dependent Tumors to Proteasome Inhibition. Clin Cancer Res. 2017 Aug 15;23(16):4817-4830. doi: 10.1158/1078-0432.CCR-16-2735.
[8] Zhao Y, Cheng Y, Qu Y. The role of EZH2 as a potential therapeutic target in retinoblastoma. Exp Eye Res. 2023 Feb;227:109389.