Structure-Based
Engineering of Irreversible Inhibitors
against Histone Lysine Demethylase KDM5A
Version 2 2018-11-15, 15:19Version 2 2018-11-15, 15:19
Version 1 2018-11-14, 21:47Version 1 2018-11-14, 21:47
Posted on 2018-11-15 - 15:19
The
active sites of hundreds of human α-ketoglutarate (αKG)
and Fe(II)-dependent dioxygenases are exceedingly well preserved,
which challenges the design of selective inhibitors. We identified
a noncatalytic cysteine (Cys481 in KDM5A) near the active sites of
KDM5 histone H3 lysine 4 demethylases, which is absent in other histone
demethylase families, that could be explored for interaction with
the cysteine-reactive electrophile acrylamide. We synthesized analogs
of a thienopyridine-based inhibitor chemotype, namely, 2-((3-aminophenyl)(2-(piperidin-1-yl)ethoxy)methyl)thieno[3,2-b]pyridine-7-carboxylic acid (N70) and a derivative
containing a (dimethylamino)but-2-enamido)phenyl moiety (N71) designed to form a covalent interaction with Cys481. We characterized
the inhibitory and binding activities against KDM5A and determined
the cocrystal structures of the catalytic domain of KDM5A in complex
with N70 and N71. Whereas the noncovalent
inhibitor N70 displayed αKG-competitive inhibition
that could be reversed after dialysis, inhibition by N71 was dependent on enzyme concentration and persisted even after dialysis,
consistent with covalent modification.
CITE THIS COLLECTION
DataCite
DataCiteDataCite
3 Biotech3 Biotech
3D Printing in Medicine3D Printing in Medicine
3D Research3D Research
3D-Printed Materials and Systems3D-Printed Materials and Systems
4OR4OR
AAPG BulletinAAPG Bulletin
AAPS OpenAAPS Open
AAPS PharmSciTechAAPS PharmSciTech
Abhandlungen aus dem Mathematischen Seminar der Universität HamburgAbhandlungen aus dem Mathematischen Seminar der Universität Hamburg
ABI Technik (German)ABI Technik (German)
Academic MedicineAcademic Medicine
Academic PediatricsAcademic Pediatrics
Academic PsychiatryAcademic Psychiatry
Academic QuestionsAcademic Questions
Academy of Management DiscoveriesAcademy of Management Discoveries
Academy of Management JournalAcademy of Management Journal
Academy of Management Learning and EducationAcademy of Management Learning and Education
Academy of Management PerspectivesAcademy of Management Perspectives
Academy of Management ProceedingsAcademy of Management Proceedings
Academy of Management ReviewAcademy of Management Review
Horton, John R.; Woodcock, Clayton B.; Chen, Qin; Liu, Xu; Zhang, Xing; Shanks, John; et al. (2018). Structure-Based
Engineering of Irreversible Inhibitors
against Histone Lysine Demethylase KDM5A. ACS Publications. Collection. https://doi.org/10.1021/acs.jmedchem.8b01219