Discovery of Potent and Oral Bioavailable MAT2A Inhibitors for the Treatment of MTAP-Deleted Tumors

被引：3

作者：

Li, Qun ^{[1
]}

Zang, Yang ^{[1
]}

An, Dan ^{[1
]}

Liu, Lifei ^{[1
]}

Jiang, Wen ^{[1
]}

Liu, Rongchen ^{[1
]}

Su, Jiangtao ^{[2
]}

Yang, Jun ^{[1
,3
,4
]}

Li, Lie ^{[1
]}

Zhang, Xuejun ^{[1
]}

机构：

[1] Hubei Biopharmaceut Ind Technol Inst Inc, Wuhan 430075, Hubei, Peoples R China

[2] Hubei Univ Technol, Wuhan 430068, Peoples R China

[3] Humanwell Healthcare Grp Co Ltd, Wuhan 430075, Hubei, Peoples R China

[4] Humanwell Pharmaceut US Inc, Ballwin, MO 63011 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2023年 / 14卷 / 12期

关键词：

Allosteric Inhibitor; Methionine Adenosyltransferase2A (MAT2A); Methylthioadenosine Phosphorylase (MTAP); 5'-Methylthioadenosine (MTA); 3H-Pyrido[1,2-c]pyrimidin-3-one; METHYLTRANSFERASE; METHIONINE;

D O I：

10.1021/acsmedchemlett.3c00488

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibition of methionine adenosyltransferase 2A (MAT2A) has received significant interest because of its implication as a synthetic lethal target in methylthioadenosine phosphorylase (MTAP)-deleted cancers. Here, we report the discovery of a series of 3H-pyrido-[1,2-c]-pyrimidin-3-one derivatives as novel MAT2A inhibitors. The selected compound 30 exhibited high potency for MAT2A inhibition and a favorable pharmacokinetic profile. Furthermore, in an HCT-116 MTAP-deleted xenograft model, compound 30 showed better in vivo potency than current clinical compound AG-270.

引用

页码：1876 / 1881

页数：6

共 50 条

[21] Discovery of AMG 193, an MTA-Cooperative PRMT5 Inhibitor for the Treatment of MTAP-Deleted Cancers
Pettus, Liping H.
Bourbeau, Matthew
Tamayo, Nuria A.
Amegadzie, Albert
Beylkin, Diane
Booker, Shon K.
Butler, John
Frohn, Michael J.
Kaller, Matthew R.
Kohn, Todd
Lanman, Brian A.
Li, Kexue
Liu, Qingyian
Ma, Vu
Medina, Jose
Minatti, Ana E.
Lopez, Patricia
Manoni, Francesco
Pickrell, Alex
Weires, Nicholas
Andersson, Jan
Cowland, Sanne
Glad, Sanne
Sarvary, Ian
Vestergaard, Mikkel
Li, Weikun
Ghimire-Rijal, Sudipa
Mardirossian, Narbe
Mukund, Susmith
Chen, Qing
Lo, Mei-Chu
Ngo, Rachel
Khetan, Jawahar
Madoux, Franck
Sanders, Christiana
Sharma, Pooja
Wang, Paul
Bruenner, Bernd
Mccloud, Stuart
Ponce, Manuel
Soto, Marcus
Wahlstrom, Jan
Xie, Fang
Yang, Yajing
Liu, Siyuan
Tan, Hong
Policheni, Antonia
Caenepeel, Sean
Slemmons, Katherine K.
Belmontes, Brian
JOURNAL OF MEDICINAL CHEMISTRY, 2025,
[22] Phase I Multicenter Clinical Trial of S095035 (MAT2A inhibitor) in Adult Participants with Advanced or Metastatic MTAP Deleted Solid Tumors
Lemech, Charlotte
Vandross, Andrae
Ervin-Haynes, Annette
Darcel, Pauline
Baron, Eric
Gailledrat, Marine
Costa, Ana
Sadou-Dubourgnoux, Amel
Ameratunga, Malaka
ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY, 2024, 20 : 47 - 48
[23] Structure-Based Discovery of a Series of Novel MAT2a Inhibitors
Zhou, Yushan
Wang, Li
Ren, Ruyue
Zhang, Junjie
Huan, Xiajuan
Yang, Peng
Miao, Ze-Hong
Xiong, Bing
Wang, Yingqing
Liu, Tongchao
ACS MEDICINAL CHEMISTRY LETTERS, 2025,
[24] Targeting MTAP-deleted tumor via synthetic lethality with a combination of a PRMT5i and an MAT2Ai
Zhang, Guiping
Li, Jiapeng
Li, Jie Jack
CANCER RESEARCH, 2024, 84 (06)
[25] Fragment-Based Design of a Potent MAT2a Inhibitor and in Vivo Evaluation in an MTAP Null Xenograft Model
De Fusco, Claudia
Schimpl, Marianne
Borjesson, Ulf
Cheung, Tony
Collie, Iain
Evans, Laura
Narasimhan, Priyanka
Stubbs, Christopher
Vazquez-Chantada, Mercedes
Wagner, David J.
Grondine, Michael
Sanders, Matthew G.
Tentarelli, Sharon
Underwood, Elizabeth
Argyrou, Argyrides
Smith, James M.
Lynch, James T.
Chiarparin, Elisabetta
Robb, Graeme
Bagal, Sharan K.
Scott, James S.
JOURNAL OF MEDICINAL CHEMISTRY, 2021, 64 (10) : 6814 - 6826
[26] Discovery of potent selective oral ACSS2 inhibitors for the treatment of acetate avid tumors
Goutopoulos, Andreas
Erez, Omri
Nakache, Philippe
Alchanati, Iris
Hay-Koren, Avital
Paz, Dikla
Kovalerchik, Dimitri
Oppenheimer, Hannah
Gottlieb, Eyal
Botti, Simone
Mor, Inbal
Pastukh, Nina
CANCER RESEARCH, 2020, 80 (16)
[27] Discovery of potent and bioavailable pan-Pim inhibitors for treatment of cancer
Hu, Huiyong
Chan, Grace
Chang, Jae
Do, Steven
Drummond, Jake
Ebens, Allen
Kolesnikov, Aleksandr
Lee, Wendy
Ly, Justin
Lyssikatos, Joseph
Murray, Jeremy
Moffat, John
Chao, Qi
Tsui, Vickie
Wallweber, Heidi
Wang, Xiaojing
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2014, 248
[28] Biochemical characterization of TNG908 as a novel, potent MTA-cooperative PRMT5 inhibitor for the treatment of MTAP-deleted cancers
Zhang, W.
Gong, S.
Cottrell, K.
Briggs, K.
Tonini, M.
Gu, L.
Whittington, D.
Yuan, H.
Gotur, D.
Jahic, H.
Huang, A.
Maxwell, J.
Mallender, W.
EUROPEAN JOURNAL OF CANCER, 2022, 174 : S26 - S26
[29] Discovery of Potent, Selective, and Orally Bioavailable DYRK2 Inhibitors for the Treatment of Prostate Cancer
Yuan, Kai
Xia, Fei
Li, Qiannan
Zheng, Mingming
Shen, Hongtao
Chen, Weijiao
Yang, Huanaoyu
Zhuang, Xujie
Zhang, Xiao-Yu
Xiao, Yibei
Yang, Peng
JOURNAL OF MEDICINAL CHEMISTRY, 2023, 66 (23) : 16235 - 16256
[30] Discovery of novel MAT2A inhibitors by an allosteric site-compatible fragment growing approach
Gao, Feng
Ding, Xiaoyu
Cao, Zhongying
Zhu, Wei
Fan, Yaya
Steurer, Barbara
Wang, Hailong
Cai, Xin
Zhang, Man
Aliper, Alex
Ren, Feng
Ding, Xiao
Zhavoronkov, Alex
BIOORGANIC & MEDICINAL CHEMISTRY, 2024, 100

← 1 2 3 4 5 →