Structure-Based Design and Synthesis of Potent and Selective KRAS G12D Inhibitors

被引：4

作者：

Cheng, Hengmiao ^{[1
]}

Li, Puhui ^{[1
]}

Chen, Ping ^{[1
]}

Irimia, Adriana ^{[1
]}

Bae, Jae Hyun ^{[1
]}

Brooun, Alexei ^{[1
]}

Fagan, Patrick ^{[1
]}

Lam, Richard ^{[1
]}

Lin, Bingzhen ^{[1
]}

Zhang, Jingchuan ^{[1
]}

Zhan, Xuejun ^{[2
]}

Wu, Xu ^{[2
]}

Xie, Nan ^{[3
]}

Chiang, Gary ^{[1
]}

Shoemaker, Robert ^{[1
]}

Vernier, Jean-Michel ^{[1
]}

机构：

[1] Erasca Inc, San Diego, CA 92121 USA

[2] Wuxi AppTec Wuhan Co Ltd, Wuhan 430075, Hubei, Peoples R China

[3] Wuxi AppTec Shanghai Co Ltd, Shanghai 200131, Peoples R China

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2023年 / 14卷 / 10期

关键词：

KRAS; G12D selective inhibitor; ERAS-5024; SBDD; PDAC; anti-tumor efficacy;

D O I：

10.1021/acsmedchemlett.3c00245

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

KRAS G12D mutation has been found in approximately 45% of pancreatic ductal adeno-carcinoma (PDAC) cases, making it an attractive therapeutic target. Through structure-based drug design, a series of potent and selective KRAS G12D inhibitors were designed. The lead compound, ERAS-5024, inhibited ERK1/2 phosphorylation and cell proliferation in three-dimensional Cell-Titer Glo assays in AsPC-1 PDAC cells with single-digit nanomolar potency and caused tumor regression in the in vivo efficacy studies. We describe here the details of the design and synthesis program that led to the discovery of ERAS-5024.

引用

页码：1351 / 1357

页数：7

共 50 条

[21] Structure-based design of potent and selective tankyrase inhibitors to target the Wnt pathway
Chakka, Nagasree
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2014, 248
[22] Structure-based design and discovery of potent and selective KDM5 inhibitors
Nie, Zhe
Shi, Lihong
Lai, Chon
O'Connell, Shawn M.
Xu, Jiangchun
Stansfield, Ryan K.
Hosfield, David J.
Veal, James M.
Stafford, Jeffrey A.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2018, 28 (09) : 1490 - 1494
[23] Structure-based design of potent and selective tankyrase inhibitors to target the Wnt pathway
Hua, Zihao
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2014, 248
[24] Structure-Based Design of Potent and Selective Leishmania N-Myristoyltransferase Inhibitors
Hutton, Jennie A.
Goncalves, Victor
Brannigan, James A.
Paape, Daniel
Wright, Megan H.
Waugh, Thomas M.
Roberts, Shirley M.
Bell, Andrew S.
Wilkinson, Anthony J.
Smith, Deborah F.
Leatherbarrow, Robin J.
Tate, Edward W.
JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (20) : 8664 - 8670
[25] Structure-based design, synthesis, and biological evaluation of potent and selective macrocyclic checkpoint kinase 1 inhibitors
Tao, Zhi-Fu
Wang, Le
Stewart, Kent D.
Chen, Zehan
Gu, Wendy
Bui, Mai-Ha
Merta, Philip
Zhang, Haiying
Kovar, Peter
Johnson, Eric
Park, Chang
Judge, Russell
Rosenberg, Saul
Sowin, Thomas
Lin, Nan-Horng
JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (07) : 1514 - 1527
[26] Structure-Based Design of Selective Noncovalent CDK12 Inhibitors
Johannes, Jeffrey W.
Denz, Christopher R.
Su, Nancy
Wu, Allan
Impastato, Anna C.
Mlynarski, Scott
Varnes, Jeffrey G.
Prince, D. Bryan
Cidado, Justin
Gao, Ning
Haddrick, Malcolm
Jones, Natalie H.
Li, Shaobin
Li, Xiuwei
Liu, Yang
Nguyen, Toan B.
O'Connell, Nichole
Rivers, Emma
Robbins, Daniel W.
Tomlinson, Ronald
Yao, Tieguang
Zhu, Xiahui
Ferguson, Andrew D.
Lamb, Michelle L.
Manchester, John I.
Guichard, Sylvie
CHEMMEDCHEM, 2018, 13 (03) : 231 - 235
[27] Potent and Selective Covalent Quinazoline Inhibitors of KRAS G12C
Zeng, Mei
Lu, Jia
Li, Lianbo
Feru, Frederic
Quan, Chunshan
Gero, Thomas W.
Ficarro, Scott B.
Xiong, Yuan
Ambrogio, Chiara
Paranal, Raymond M.
Catalano, Marco
Shao, Jay
Wong, Kwok-Kin
Marto, Jarrod A.
Fischer, Eric S.
Janne, Pasi A.
Scott, David A.
Westover, Kenneth D.
Gray, Nathanael S.
CELL CHEMICAL BIOLOGY, 2017, 24 (08): : 1005 - +
[28] Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors
Waldschmidt, Helen V.
Homan, Kristoff T.
Cruz-Rodriez, Osvaldo
Cato, Marilyn C.
Waninger-Saroni, Jessica
Larimore, Kelly M.
Cannavo, Alessandro
Song, Jianliang
Cheung, Joseph Y.
Kirchhoff, Paul D.
Koch, Walter J.
Tesmer, John J. G.
Larsen, Scott D.
JOURNAL OF MEDICINAL CHEMISTRY, 2016, 59 (08) : 3793 - 3807
[29] Inhibition of KRAS G12D mutant with small molecules
Lee, Dae-Hee
Lee, Ji Yoon
CANCER RESEARCH, 2024, 84 (06)
[30] KRAS G12D mutation in Brunner gland adenoma
Ortega, Mahatma
Sparks, Jessica
Lichy, Jack
Nava, Victor E.
BMJ CASE REPORTS, 2023, 16 (01)

← 1 2 3 4 5 →