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A protein crystallography and small molecule informatics‐based discovery engine for the development of selective chemical probes for in vivo investigations of protein kinases (968.3)
Author(s) -
GrumTokars Valerie,
Roy Saktimayee,
Minasov George,
Anderson Wayne,
Watterson D.
Publication year - 2014
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.28.1_supplement.968.3
Subject(s) - kinome , in vivo , small molecule , p38 mitogen activated protein kinases , kinase , chemical biology , drug discovery , chemistry , computational biology , mapk/erk pathway , microbiology and biotechnology , biochemistry , biology , genetics
There is a critical need for selective serine‐threonine protein kinase (S/T PK) inhibitors appropriate for in vivo studies. We used a discovery engine based on high resolution co‐crystallography of PKs in complex with ligands and robust databases for small molecules with documented in vivo properties and potential for good ADMET property development (Chico et al., 2009a, 2009b). As a proof‐of‐concept, we targeted the active site of the stress activated p38α MAPK, a well‐studied target that has been intractable for PK specificity when targeting the active site. Further, we focused on the especially difficult challenge of p38α MAPK involvement in CNS pathology progression where it is activated by diverse stressors in both glia and neurons as part of a synaptic dysfunction cycle. Novel, highly selective, CNS penetrant, active site bound, p38α MAPK inhibitors were developed and validated by large scale kinome and pharmacological screens, cellular target engagement, and in vivo proof of efficacy (Watterson et al., 2013). Grant Funding Source : NIH grants R01 NS056051, R01 AG031311, U01 AG043415