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A Conserved Ser/Thr Kinase from Malaria Parasites is Inhibited by Tyrosine Kinase Inhibitors
Author(s) -
Kirkman Lucy,
Perez Astrid,
Lin Benjamin,
Harris Darcy,
Schermerhorn Janse,
Qian Yiwen,
Brandt Gabriel
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.921.13
Subject(s) - kinase , biochemistry , protein kinase domain , cyclin dependent kinase 9 , map2k7 , tyrosine kinase , map kinase kinase kinase , mitogen activated protein kinase kinase , biology , chemistry , protein kinase a , cyclin dependent kinase 2 , signal transduction , mutant , gene
Inhibitors were identified for a Ser/Thr kinase shared by all malaria parasites and shown to be essential. This kinase has a number of unusual sequence features, one of which is a gatekeeper residue much more commonly associated with eukaryotic tyrosine kinases than serine/threonine kinases. The recombinant kinase domain was expressed and purified from E. coli, then screened against a library of small molecules including known Ser/Thr and Tyr kinase inhibitors. The compounds emerging from the screen as potential inhibitors were all compounds with reported activity against Tyr kinases. An enzyme‐coupled assay was used to establish the affinity of each of these compounds. The most potent is a relatively high‐affinity inhibitor of the recombinant kinase domain (Ki = 1.2 uM). Comparison of a small family of selected analogs shows that the kinase discriminates among them, allowing the first view of the pharmacophore of this kinase. These are the first reported inhibitors of any member of this class of kinases and thus represent potential lead compounds for the development of new anti‐malarials. Support or Funding Information Franklin Research Grant (American Philosophical Society) Hackman Fund (Franklin & Marshall College) Eyler Fund (Franklin & Marshall College) Marshall Scholarship (Franklin & Marshall College) Leser Scholarship (Franklin & Marshall College)