Journal of Medicinal Chemistry p. 11448 - 11468 (2020)
Update date:2022-08-03
Topics:
Lawson, Kenneth V.
Kalisiak, Jaroslaw
Lindsey, Erick A.
Newcomb, Eric T.
Leleti, Manmohan Reddy
Debien, Laurent
Rosen, Brandon R.
Miles, Dillon H.
Sharif, Ehesan U.
Jeffrey, Jenna L.
Tan, Joanne B. L.
Chen, Ada
Zhao, Sharon
Xu, Guifen
Fu, Lijuan
Jin, Lixia
Park, Tim W.
Berry, Wade
Moschütz, Susanne
Scaletti, Emma
Str?ter, Norbert
Walker, Nigel P.
Young, Stephen W.
Walters, Matthew J.
Schindler, Uli
Powers, Jay P.
Extracellular adenosine (ADO), present in high concentrations in the tumor microenvironment (TME), suppresses immune function via inhibition of T cell and NK cell activation. Intratumoral generation of ADO depends on the sequential catabolism of ATP by two ecto-nucleotidases, CD39 (ATP → AMP) and CD73 (AMP → ADO). Inhibition of CD73 eliminates a major pathway of ADO production in the TME and can reverse ADO-mediated immune suppression. Extensive interrogation of structure-activity relationships (SARs), structure-based drug design, and optimization of pharmacokinetic properties culminated in the discovery of AB680, a highly potent (Ki = 5 pM), reversible, and selective inhibitor of CD73. AB680 is further characterized by very low clearance and long half-lives across preclinical species, resulting in a PK profile suitable for long-acting parenteral administration. AB680 is currently being evaluated in phase 1 clinical trials. Initial data show AB680 is well tolerated and exhibits a pharmacokinetic profile suitable for biweekly (Q2W) iv-administration in human.
View MoreZhejiang Chemline International Co., Ltd.
Contact:+86-571-88062298
Address:Hengdian Industry Area, Dongyang, Zhejiang, China
Hangzhou Fortune Biopharm Co.,LTD.
website:http://www.ftpharm.com
Contact:86-571-87621708
Address:279 Zixuan Road,Xihu District,Hangzhou,Zhejiang(310030),China.
Contact:86-898-65311214
Address:Room 102, BLDG. 68 Jiangnan City, No. 66 Heping Road,Haikou, Hainan, China
Arshine Pharmaceutical Co., Limited
website:http://www.cnarshine.com
Contact:0731-88503671
Address:Room 1109.Block C3, Lugu Enterprise Plaza,No.27 Wenxuan Road,Changsha National Hi-Tech Industrial Development Zone,Hunan ,P.R.China
WENZHOU M&C FOREIGN TRADE CO.,LTD.
Contact:+86-577-88862917
Address:No.8 Liming West Road,Wenzhou,zhejiang,China
Doi:10.1021/ol051599g
(2005)Doi:10.1021/ja0525096
(2005)Doi:10.1016/j.bmc.2005.05.053
(2005)Doi:10.1002/hlca.19380210195
(1938)Doi:10.1021/acs.orglett.0c00239
(2020)Doi:10.1002/hlca.19830660326
(1983)