Discovery of A-910, a Highly Potent and Orally Bioavailable Dual MerTK/Axl-Selective Tyrosine Kinase Inhibitor

被引：0

作者：

Yu, Yiyun ^{[1
]}

Jang, Miyeon ^{[2
]}

Miyashiro, Julie ^{[1
]}

Clark, Richard F. ^{[1
]}

Zhu, Gui-Dong ^{[1
]}

Gong, Jane ^{[1
]}

Dai, Yujia ^{[1
]}

Frey, Robin R. ^{[1
]}

Penning, Thomas D. ^{[1
]}

Kim, Hadong ^{[2
]}

Lee, Hyung Ki ^{[2
]}

Kim, Jin Kwan ^{[2
]}

Ryu, Ki Moon ^{[2
]}

Park, Seong Jin ^{[2
]}

Yoon, Taeyoung ^{[2
]}

Li, Tao ^{[1
]}

Kurnick, Matthew D. ^{[1
]}

Kapecki, Nicolas J. ^{[1
]}

Li, Leiming ^{[1
]}

Gorman, Jacob V. ^{[1
]}

Montgomery, Debra A. ^{[1
]}

Manaves, Vlasios ^{[1
]}

Bromberg, Kenneth D. ^{[1
]}

Doktor, Stella Z. ^{[1
]}

Thakur, Ashish ^{[1
]}

Wang, Jin ^{[1
]}

Smith, Heath A. ^{[1
]}

Buchanan, Fritz G. ^{[1
]}

Ferguson, Debra C. ^{[1
]}

Torrent, Maricel ^{[1
]}

Jakob, Clarissa G. ^{[1
]}

Qiu, Wei ^{[1
]}

Upadhyay, Anup K. ^{[1
]}

Martin, Ruth L. ^{[1
]}

Lai, Albert ^{[1
]}

Michaelides, Michael R. ^{[1
]}

机构：

[1] Abbvie Inc, N Chicago, IL 60064 USA

[2] Dong A ST, Yongin 17073, Gyeonggi Do, South Korea

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年

关键词：

TAM FAMILY; PYRIMIDINES; AXL;

D O I：

10.1021/acs.jmedchem.4c01450

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

TAM receptor tyrosine kinases have emerged as promising therapeutic targets for cancer treatment due to their roles in both tumor intrinsic survival mechanisms and suppression of antitumor immunity within the tumor microenvironment. Inhibiting MerTK and Axl selectively is believed to hinder cancer cell survival, reverse the protumor myeloid phenotype, and suppress efferocytosis, thereby eliciting an antitumor immune response. In this study, we present the discovery of A-910, a highly potent and selective dual MerTK/Axl inhibitor, achieved through a structure-based medicinal chemistry campaign. The lead compound exhibits favorable oral bioavailability, exceptional kinome selectivity, and significantly improved in vivo target engagement. These findings support the use of A-910 as an orally bioavailable in vivo tool compound for investigating the immunotherapy potential of dual MerTK/Axl inhibition.

引用

页数：33

共 50 条

[1] Discovery of a Pyrimidinedione Derivative as a Potent and Orally Bioavailable Axl Inhibitor
Zhang, Hefeng
Peng, Xia
Dai, Yang
Shao, Jingwei
Ji, Yinchun
Sun, Yiming
Liu, Bo
Cheng, Xu
Ai, Jing
Duan, Wenhu
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2021, 64 (07) : 3956 - 3975
[2] Discovery of GSK143, a highly potent, selective and orally efficacious spleen tyrosine kinase inhibitor
Liddle, John
Atkinson, Francis L.
Barker, Michael D.
Carter, Paul S.
Curtis, Neil R.
Davis, Rob P.
Douault, Clement
Dickson, Marion C.
Elwes, Dorothy
Garton, Neil S.
Gray, Matthew
Hayhow, Thomas G.
Hobbs, Clare I.
Jones, Emma
Leach, Stuart
Leavens, Karen
Lewis, Huw D.
McCleary, Scott
Neu, Margarete
Patel, Vipulkumar K.
Preston, Alex G. S.
Ramirez-Molina, Cesar
Shipley, Tracy J.
Skone, Philip A.
Smithers, Nick
Somers, Donald O.
Walker, Ann L.
Watson, Robert J.
Weingarten, Gordon G.
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2011, 21 (20) : 6188 - 6194
[3] Discovery of a Potent, Selective, and Orally Bioavailable Pyridinyl-Pyrimidine Phthalazine Aurora Kinase Inhibitor
Cee, Victor J.
Schenkel, Laurie B.
Hodous, Brian L.
Deak, Holly L.
Nguyen, Hanh N.
Olivieri, Philip R.
Romero, Karina
Bak, Annette
Be, Xuhai
Bellon, Steve
Bush, Tammy L.
Cheng, Alan C.
Chung, Grace
Coats, Steve
Eden, Patrick M.
Hanestad, Kelly
Gallant, Paul L.
Gu, Yan
Huang, Xin
Kendall, Richard L.
Lin, Min-Hwa Jasmine
Morrison, Michael J.
Patel, Vinod F.
Radinsky, Robert
Rose, Paul E.
Ross, Sandra
Sun, Ji-Rong
Tang, Jin
Zhao, Huilin
Payton, Marc
Geuns-Meyer, Stephanie D.
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (17) : 6368 - 6377
[4] Discovery of PF-04457845: A Highly Potent, Orally Bioavailable, and Selective Urea FAAH Inhibitor
Johnson, Douglas S.
Stiff, Cory
Lazerwith, Scott E.
Kesten, Suzanne R.
Fay, Lorraine K.
Morris, Mark
Beidler, David
Liimatta, Marya B.
Smith, Sarah E.
Dudley, David T.
Sadagopan, Nalini
Bhattachar, Shobha N.
Kesten, Stephen J.
Nomanbhoy, Tyzoon K.
Cravatt, Benjamin F.
Ahn, Kay
[J]. ACS MEDICINAL CHEMISTRY LETTERS, 2011, 2 (02): : 91 - 96
[5] Discovery and characterization of potent and selective AXL receptor tyrosine kinase inhibitor AB801
Miles, D.
Paprcka, S.
Foley, C.
Qu, S.
Lamani, M.
Paladugu, S.
Huang, H. T.
Tibrewal, N.
Chen, A.
Kulusich, J.
Garrido-Shaqfeh, S.
Fabila, P.
Sridhar, S.
Liu, S.
Swinarski, D.
Zhao, X.
Fernandez-Salas, E.
Green, D.
Jin, L.
Leleti, M.
[J]. EUROPEAN JOURNAL OF CANCER, 2022, 174 : S103 - S103
[6] UNC5293, a potent, orally available and highly MERTK-selective inhibitor
Zheng, Hongchao
Zhao, Jichen
Li, Bing
Zhang, Weihe
Stashko, Michael A.
Minson, Katherine A.
Huey, Madeline G.
Zhou, Yubai
Earp, Henry Shelton
Kireev, Dmitri
Graham, Douglas K.
DeRyckere, Deborah
Frye, Stephen, V
Wang, Xiaodong
[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2021, 220
[7] Discovery of a Highly Potent and Orally Bioavailable STAT3 Dual Phosphorylation Inhibitor for Pancreatic Cancer Treatment
He, Peng
Bian, Aiwu
Miao, Ying
Jin, Wangrui
Chen, Huang
He, Jia
Li, Liting
Sun, Yue
Ye, Jiangnan
Yi, Zhengfang
Zhou, Wenbo
Chen, Yihua
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2022, : 15487 - 15511
[8] Discovery of a highly selective, orally bioavailable, brainpenetrant LRRK2 Inhibitor
Gasser, Thomas
Oprea, Tudor
Kahle, Philipp
Dahl, Bernadette
Riebenbauer, Benjamin
Bertoli, Federico
Izzi, Francesca
Deleidi, Michela
Mochalov, Stepan
Bulanova, Elena
Ryakhovskiy, Alexey
Kysil, Volodymyr
Dukes, Iain
Savchuk, Nikolay
Karapetian, Ruben
Guaitoli, Giambattista
Gloeckner, Christian-Johannes
Pushechnikov, Alexei
[J]. MOVEMENT DISORDERS, 2023, 38 : S7 - S7
[9] Discovery of AS-1763: A Potent, Selective, Noncovalent, and Orally Available Inhibitor of Bruton's Tyrosine Kinase
Kawahata, Wataru
Asami, Tokiko
Kiyoi, Takao
Irie, Takayuki
Kashimoto, Shigeki
Furuichi, Hatsuo
Sawa, Masaaki
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2021, 64 (19) : 14129 - 14141
[10] Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable γ-Secretase Inhibitor
Gillman, Kevin W.
Starrett, John E., Jr.
Parker, Michael F.
Xie, Kai
Bronson, Joanne J.
Marcin, Lawrence R.
McElhone, Kate E.
Bergstrom, Carl P.
Mate, Robert A.
Williams, Richard
Meredith, Jere E., Jr.
Burton, Catherine R.
Barten, Donna M.
Toyn, Jeremy H.
Roberts, Susan B.
Lentz, Kimberley A.
Houston, John G.
Zaczek, Robert
Albright, Charles F.
Decicco, Carl P.
Macor, John E.
Olson, Richard E.
[J]. ACS MEDICINAL CHEMISTRY LETTERS, 2010, 1 (03): : 120 - 124

← 1 2 3 4 5 →