Abstract：Protein arginine methyltransferase 5 (PRMT5) is an important member of protein arginine methyltransferases (PRMTs) family. In a variety of human malignant tumors, including lung cancer, ovarian cancer, colorectal cancer, breast cancer, melanoma, leukemia and malignant glioma, the expression of PRMT5 is up-regulated. In addition, PRMT5 has been confirmed as an anti-tumor target for mantle cell lymphoma (MCL) and glioblastoma. The study of anti-tumor small molecule inhibitors targeting PRMT5 has attracted more and more attention. This paper reviews the research progress of small molecule inhibitors of PRMT5 found in recent years, and provides reference for drug design and discovery.
李慧, 邹毅, 宋利, 唐海, 徐云根. 蛋白质精氨酸甲基转移酶5小分子抑制剂的研究进展[J]. 中国药学杂志, 2022, 57(7): 517-523.
LI Hui, ZOU Yi, SONG Li, TANG Hai, XU Yun-gen. Research Progress in Small Molecular Inhibitors of PRMT5. Chinese Pharmaceutical Journal, 2022, 57(7): 517-523.
YANG Y, BEDFORD M T. Protein arginine methyltransferases and cancer [J]. Nat Rev Cancer, 2013, 13(1):37-50.
[2]
ALINARI L, MAHASENAN K V, YAN F, et al. Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation [J]. Blood, 2015, 125(16):2530-2543.
[3]
BRANSCOMBE T L, FRANKEL A, LEE J H, et al. PRMT5 (Janus kinase-binding protein 1)catalyzes the formation of symmetric dimethylarginine residues inproteins [J]. J Biol Chem, 2001, 276(35):32971-32976.
[4]
YUAN Y, NIE H. Protein arginine methyltransferase 5: a potential cancer therapeutic target [J]. Cell Oncol(Pordr), 2021, 44(1):33-44.
[5]
LIN W J, GARY J D, YANG M C, et al. The mammalian immediate-early TIS21 protein and the leukemia-associated BTG1 protein interact with a protein-arginine N-methyltransferase [J]. J Biol Chem, 1996, 271(25):15034-15044.
[6]
BEDFORD M T, RICHARD S. Arginine methylation an emerging regulator of protein function [J]. Mol Cell, 2005, 18(3):263-272.
[7]
ANTONYSAMY S, BONDAY Z, CAMPBELL R M, et al. Crystal structure of the human PRMT5:MEP50 complex [J]. Proc Natl Acad Sci USA, 2012, 109(44):17960-17965.
[8]
BAO S, QYANG Y, YANG P, et al. The highly conserved protein methyltransferase, Skb1, is a mediator of hyperosmotic stress response in the fission yeast Schizosaccharomyces pombe [J]. J Biol Chem, 2001, 276(18):14549-14552.
[9]
ICKMANS K, CLARYS P, NIJS J, et al. Association between cognitive performance, physical fitness, and physical activity level in women with chronic fatigue syndrome [J]. J Rehabil Res Dev, 2013, 50(6):795-810.
[10]
TABATA T, KOKURA K, TEN DIJKE P, et al. Ski co-repressor complexes maintain the basal repressed state of the TGF-beta target gene, SMAD7, via HDAC3 and PRMT5 [J]. Genes Cells, 2009, 14(1):17-28.
[11]
RICHARD S, MOREL M, CLEROUX P. Arginine methylation regulates IL-2 gene expression: a role for protein arginine methyltransferase 5 (PRMT5) [J]. Biochem J, 2005, 388 (Pt1):379-386.
[12]
KWAK Y T, GUO J, PRAJAPATI S, et al. Methylation of SPT5 regulates its interaction with RNA polymerase Ⅱ and transcriptional elongation properties [J]. Mol Cell, 2003, 11(4):1055-1066.
[13]
TEE W W, PARDO M, THEUNISSEN T W, et al. Prmt5 is essential for early mouse development and acts in the cytoplasm to maintain ES cell pluripotency [J]. Genes Dev, 2010, 24(24):2772-2777.
[14]
CHIANG K, ZIELINSKA A E, SHAABAN A M, et al. PRMT5 is a critical regulator of breast cancer stem cell function via histone methylation and FOXP1 expression [J]. Cell Rep, 2017, 21(12):3498-3513.
[15]
JING P Y, ZHAO N, YE M X, et al. Protein arginine methyltransferase 5 promotes lung cancer metastasis via the epigenetic regulation of miR-99 family/FGFR3 signaling [J]. Cancer Lett, 2018, 427: 38-48.
[16]
LIU L, ZHAO X P, ZHAO L, et al. Arginine methylation of SREBP1a via PRMT5 promotes de novo lipogenesis and tumor growth [J]. Cancer Res, 2016, 76(5):1260-1272.
[17]
LIN H, LUENGO J I. Nucleoside protein arginine methyltransferase 5 (PRMT5) inhibitors [J]. Bioorg Med Chem Lett, 2019, 29(11):1264-1269.
[18]
WU T M H, GAFFNEY D, BEKE L, et al. JNJ-64619178, a selective and pseudo-irreversible PRMT5 inhibitor with potent in vitro and in vivo activity, demonstrated in several lung cancer models [C]. Philadelphia (PA): AACR, 2018: 4859-4859.
[19]
BONDAY Z Q, CORTEZ G S, GROGAN M J, et al. LLY-283, a Potent and selective inhibitor of arginine methyltransferase 5, PRMT5, with antitumor activity [J]. ACS Med Chem Lett, 2018, 9(7):612-617.
[20]
AHNERT J R P, PEREZ C A, WONG K M, et al. PFu06939999, a potent and selective PRMT5 inhibitor, in patients with advanced or metastatic solid tumors: a phase 1 dose escalation study [C]. Chicago, ASCO, 2021:3019-3019.
[21]
LUENGO J. Preparation of Nucleosides as Selective Inhibitors of Protein Arginine Methyltransferase 5: American, WO2018152548 A1[P]. 2018-08-23.
[22]
LUENGO J. Selective Inhibitors of Protein , Arginine Methyltransferase 5 (PRMT5):American, WO2018160824 A1 [P]. 2018-09-07.
[23]
SPANNHOFFA, HEINKE R, BAUER I, et al. Target-based approach to inhibitors of histone arginine methyltransferases [J]. J Med Chem, 2007, 50 (10): 2319-2325.
[24]
LIN H, WANG M, ZHANG Y W, et al. Discovery of potent and selective covalent protein arginine methyltransferase 5 (PRMT5) inhibitors [J]. ACS Med Chem Lett, 2019, 10(7):1033-1038.
[25]
MAO R, SHAO J, ZHU K, et al. Potent, selective, and cell active protein arginine methyltransferase 5 (PRMT5) inhibitor developed by structure-based virtual screening and hit optimization [J]. J Med Chem, 2017, 60(14):6289-6304.
[26]
ZHU K, JIANG C, TAO H, et al. Identification of a novel selective small-molecule inhibitor of protein arginine methyltransferase 5 (PRMT5) by virtual screening, resynthesis and biological evaluations [J]. Bioorg Med Chem Lett, 2018, 28(9):1476-1483.
[27]
PANDE V, SUN W, BEKE L, et al. A chemical probe for the methyl transferase PRMT5 with a novel binding mode [J]. ACS Med Chem Lett, 2020, 11(11):2227-2231.
[28]
DUNCAN K W, RIOUX N, BORIACK-SJODIN P A, et al. Structure and property guided design in the identification of PRMT5 tool compound EPZ015666 [J]. ACS Me Chem Lett, 2016, 7(2):162-166.
[29]
WANG Y, HU W, YUAN Y. Protein arginine methyltransferase 5 (PRMT5) as an anticancer target and its inhibitor discovery [J]. J Med Chem, 2018, 61(21):9429-9441.
[30]
WATTS J M B, T J, THOMASSEN A, et al. A phase Ⅰ/Ⅱ study to investigate the safety and clinical activity of the protein arginine methyltransferase 5 inhibitor GSK3326595 in subjects with myelodysplastic syndrome and acute myeloid leukemia [C]. Orlando: ASH, 2019, 134: 2656-2660.
[31]
FALK H, RC F, YE B, et al. Potent and selective PRMT5 inhibitors as potential treatment for cancers[C]. Philadelphia(PA): AACR, 2015: 5371-5371.
[32]
SHAO J, ZHU K, DU D, et al. Discovery of 2-substituted-N-(3-(3, 4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1, 2, 3, 4-tetrahydroisoquinoline-6-carboxamide as potent and selective protein arginine methyltransferases 5 inhibitors: design, synthesis and biological evaluation [J]. Eur J Med Chem, 2019, 164: 317-333.
[33]
TAO H, YAN X, ZHU K, et al. Discovery of novel PRMT5 inhibitors by virtual screening and biological evaluations [J]. Chem Pharm Bull, 2019, 67(4):382-388.
[34]
ALINARI L, MAHASENAN K V, YAN F, et al. Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation [J]. Blood, 2015, 125(16): 2530-2543.
[35]
ZHU K, JIANG C S, HU J, et al. Interaction assessments of the first S-adenosylmethionine competitive inhibitor and the essential interacting partner methylosome protein 50 with protein arginine methyltransferase 5 by combined computational methods [J]. Biochem Biophys Res Commun, 2018, 495(1):721-727.
[36]
YE Y, ZHANG B, MAO R, et al. Discovery and optimization of selective inhibitors of protein arginine methyltransferase 5 by docking-based virtual screening [J]. Org Biomol Chem, 2017, 15(17):3648-3661.
[37]
JI S, MA S, WANG W J, et al. Discovery of selective protein arginine methyltransferase 5 inhibitors and biological evaluations [J]. Chem Biol Drug Design, 2017, 89(4):585-598.
[38]
PALTE R L, SCHNEIDER S E, ALTMAN M D, et al. Allosteric modulation of protein arginine methyltransferase 5 (PRMT5) [J]. ACS Med Chem Lett, 2020, 11(9):1688-1693.
2022, Vol. 57 
