mta -协同PRMT5抑制剂AMG 193的发现治疗mtap缺失的癌症

IF 6.8 1区 医学 Q1 CHEMISTRY, MEDICINAL
Liping H. Pettus*, Matthew Bourbeau, Nuria A. Tamayo, Albert Amegadzie, Diane Beylkin, Shon K. Booker, John Butler, Michael J. Frohn, Matthew R. Kaller, Todd Kohn, Brian A. Lanman, Kexue Li, Qingyian Liu, Vu Ma, Jose Medina, Ana E. Minatti, Patricia Lopez, Francesco Manoni, Alex Pickrell, Nicholas Weires, Jan Andersson, Sanne Cowland, Sanne Glad, Ian Sarvary, Mikkel Vestergaard, Weikun Li, Sudipa Ghimire-Rijal, Narbe Mardirossian, Susmith Mukund, Qing Chen, Mei-Chu Lo, Rachel Ngo, Jawahar Khetan, Franck Madoux, Christiana Sanders, Pooja Sharma, Paul Wang, Bernd Bruenner, Stuart McCloud, Manuel Ponce, Marcus Soto, Jan Wahlstrom, Fang Xie, Yajing Yang, Siyuan Liu, Hong Tan, Antonia Policheni, Sean Caenepeel, Katherine K. Slemmons, Brian Belmontes, Paul Hughes and Jennifer R. Allen, 
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Minatti,&nbsp;Patricia Lopez,&nbsp;Francesco Manoni,&nbsp;Alex Pickrell,&nbsp;Nicholas Weires,&nbsp;Jan Andersson,&nbsp;Sanne Cowland,&nbsp;Sanne Glad,&nbsp;Ian Sarvary,&nbsp;Mikkel Vestergaard,&nbsp;Weikun Li,&nbsp;Sudipa Ghimire-Rijal,&nbsp;Narbe Mardirossian,&nbsp;Susmith Mukund,&nbsp;Qing Chen,&nbsp;Mei-Chu Lo,&nbsp;Rachel Ngo,&nbsp;Jawahar Khetan,&nbsp;Franck Madoux,&nbsp;Christiana Sanders,&nbsp;Pooja Sharma,&nbsp;Paul Wang,&nbsp;Bernd Bruenner,&nbsp;Stuart McCloud,&nbsp;Manuel Ponce,&nbsp;Marcus Soto,&nbsp;Jan Wahlstrom,&nbsp;Fang Xie,&nbsp;Yajing Yang,&nbsp;Siyuan Liu,&nbsp;Hong Tan,&nbsp;Antonia Policheni,&nbsp;Sean Caenepeel,&nbsp;Katherine K. Slemmons,&nbsp;Brian Belmontes,&nbsp;Paul Hughes and Jennifer R. Allen,&nbsp;","doi":"10.1021/acs.jmedchem.4c0312110.1021/acs.jmedchem.4c03121","DOIUrl":null,"url":null,"abstract":"<p ><i>MTAP</i> deletion occurs in 10–15% of all human cancers due to its proximity to the tumor suppressor gene <i>CDKN2A</i>. 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引用次数: 0

摘要

MTAP缺失发生在10-15%的人类癌症中,因为它接近肿瘤抑制基因CDKN2A。MTAP的缺失导致甲基硫腺苷(MTA)的积累,MTA与细胞必需蛋白精氨酸甲基转移酶5 (PRMT5)的甲基供体s -腺苷蛋氨酸(SAM)具有结构相似性。通过与SAM竞争,MTA部分抑制PRMT5,使mtap缺失的肿瘤对进一步的PRMT5抑制敏感。在此,我们报告了mta协同PRMT5抑制剂AMG 193的发现,该分子抑制HCT116 mtap缺失细胞的增殖,选择性为HCT116 MTAP-WT细胞的40倍。AMG 193对内源性MTAP-null肿瘤如BxPC-3 (96% TGI @ 100 mg/kg QD)和U87MG (88% TGI @ 100 mg/kg QD)的小鼠异种移植物口服有效。临床前数据表明AMG 193具有脑渗透性。AMG 193目前正处于I/II期临床试验,用于治疗晚期mtap缺失实体瘤。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Discovery of AMG 193, an MTA-Cooperative PRMT5 Inhibitor for the Treatment of MTAP-Deleted Cancers

Discovery of AMG 193, an MTA-Cooperative PRMT5 Inhibitor for the Treatment of MTAP-Deleted Cancers

MTAP deletion occurs in 10–15% of all human cancers due to its proximity to the tumor suppressor gene CDKN2A. The loss of MTAP leads to accumulation of methylthioadenosine (MTA), which shares structural similarity to S-adenosyl methionine (SAM), the methyl donor for the cell-essential protein arginine methyltransferase 5 (PRMT5). By competing with SAM, MTA partially inhibits PRMT5, making MTAP-deleted tumors susceptible to further PRMT5 inhibition. Herein, we report the discovery of MTA-cooperative PRMT5 inhibitor AMG 193, a molecule that inhibited the proliferation of HCT116 MTAP-deleted cells with ∼40x selectivity over HCT116 MTAP-WT cells. AMG 193 was orally efficacious in mouse xenografts of endogenous MTAP-null tumors such as BxPC-3 (96% TGI @ 100 mg/kg QD) and U87MG (88% TGI @ 100 mg/kg QD). Preclinical data indicate that AMG 193 is brain-penetrant. AMG 193 is currently in Phase I/II clinical trials for the treatment of advanced MTAP-deleted solid tumors.

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来源期刊
Journal of Medicinal Chemistry
Journal of Medicinal Chemistry 医学-医药化学
CiteScore
4.00
自引率
11.00%
发文量
804
审稿时长
1.9 months
期刊介绍: The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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