2039-67-0Relevant articles and documents
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Boekelheide,V.,Chang,M.Y.
, p. 1303 - 1307 (1964)
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Discovery of Diaminopyrimidine Carboxamide HPK1 Inhibitors as Preclinical Immunotherapy Tool Compounds
Vara, Brandon A.,Levi, Samuel M.,Achab, Abdelghani,Candito, David A.,Fradera, Xavier,Lesburg, Charles A.,Kawamura, Shuhei,Lacey, Brian M.,Lim, Jongwon,Methot, Joey L.,Xu, Zangwei,Xu, Haiyan,Smith, Dustin M.,Piesvaux, Jennifer A.,Miller, J. Richard,Bittinger, Mark,Ranganath, Sheila H.,Bennett, David J.,Dimauro, Erin F.,Pasternak, Alexander
supporting information, p. 653 - 661 (2021/04/12)
Hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase, is a negative immune regulator of T cell receptor (TCR) and B cell signaling that is primarily expressed in hematopoietic cells. Accordingly, it has been reported that HPK1 loss-of-function in HPK1 kinase-dead syngeneic mouse models shows enhanced T cell signaling and cytokine production as well as tumor growth inhibition in vivo, supporting its value as an immunotherapeutic target. Herein, we present the structurally enabled discovery of novel, potent, and selective diaminopyrimidine carboxamide HPK1 inhibitors. The key discovery of a carboxamide moiety was essential for enhanced enzyme inhibitory potency and kinome selectivity as well as sustained elevation of cellular IL-2 production across a titration range in human peripheral blood mononuclear cells. The elucidation of structure-activity relationships using various pendant amino ring systems allowed for the identification of several small molecule type-I inhibitors with promising in vitro profiles.
Synthesis of Functionalized Indolines and Dihydrobenzofurans by Iron and Copper Catalyzed Aryl C-N and C-O Bond Formation
Henry, Martyn C.,Senn, Hans Martin,Sutherland, Andrew
, p. 346 - 364 (2019/01/08)
A simple and effective one-pot, two-step intramolecular aryl C-N and C-O bond forming process for the preparation of a wide range of benzo-fused heterocyclic scaffolds using iron and copper catalysis is described. Activated aryl rings were subjected to a highly regioselective, iron(III) triflimide-catalyzed iodination, followed by a copper(I)-catalyzed intramolecular N-or O-arylation step leading to indolines, dihydrobenzofurans, and six-membered analogues. The general applicability and functional group tolerance of this method were exemplified by the total synthesis of the neolignan natural product, (+)-obtusafuran. DFT calculations using Fukui functions were also performed, providing a molecular orbital rationale for the highly regioselective arene iodination process.