329187-80-6Relevant articles and documents
Discovery of AB680: A Potent and Selective Inhibitor of CD73
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.
, p. 11448 - 11468 (2020/11/26)
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.
INHIBITORS OF CD73-MEDIATED IMMUNOSUPPRESSION
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Paragraph 0214, (2018/06/06)
Compounds that modulate the conversion of AMP to adenosine by 5'- nucleotidase, ecto, and compositions containing the compounds and methods for synthesizing the compounds, are described herein. The use of such compounds and compositions for the treatment and/or prevention of a diverse array of diseases, disorders and conditions, including cancer- and immune-related disorders, that are mediated by 5'- nucleotidase, ecto is also provided.
Method for synthesizing clofarabine
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Paragraph 0040; 0046; 0047; 0050; 0052; 0053, (2017/08/27)
The invention discloses a method for synthesizing clofarabine; the method comprises the following synthetic routes described in the specification, wherein in the formula III and the formula IV, R1 and R2 are the same or different acyl groups. The method comprises the following steps: 1) ammoniation: dissolving a compound represented by the formula III in an organic solvent, introducing ammonia gas, and carrying out a closed reaction, to obtain a compound represented by the formula IV after the reaction is completed, wherein the organic solvent is any combination of one or two or more of acetonitrile, ethyl acetate, dichloromethane and tetrahydrofuran, the concentration of ammonia gas dissolved in the organic solvent is 0.1-20 wt%, the closed reaction is carried out for 10-40 hours, and the reaction temperature is 0-100 DEG C; and 2) protecting group removal: dissolving the compound represented by the formula IV and prepared in the step 1) in alcohol, adding an alcohol solution of sodium alkoxide, carrying out a reaction, then adjusting the pH value to 6-7, cooling and crystallizing, and thus obtaining a clofarabine crude product.