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A Perspective on Medicinal Chemistry Approaches for Targeting Pyruvate Kinase M2
journal contribution
posted on 2021-11-02, 12:03 authored by Sahil Arora, Gaurav Joshi, Anuhar Chaturvedi, Michael Heuser, Santoshkumar Patil, Raj KumarThe allosteric regulation of pyruvate
kinase M2 (PKM2) affects
the switching of the PKM2 protein between the high-activity and low-activity
states that allow ATP and lactate production, respectively. PKM2,
in its low catalytic state (dimeric form), is chiefly active in metabolically
energetic cells, including cancer cells. More recently, PKM2 has emerged
as an attractive target due to its role in metabolic dysfunction and
other interrelated conditions. PKM2 (dimer) activity can be inhibited
by modulating PKM2 dimer–tetramer dynamics using either PKM2
inhibitors that bind at the ATP binding active site of PKM2 (dimer)
or PKM2 activators that bind at the allosteric site of PKM2, thus
activating PKM2 from the dimer formation to the tetrameric formation.
The present perspective focuses on medicinal chemistry approaches
to design and discover PKM2 inhibitors and activators and further
provides a scope for the future design of compounds targeting PKM2
with better efficacy and selectivity.
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pyruvate kinase m2metabolically energetic cellsmedicinal chemistry approachesincluding cancer cellsdimeric form ),attractive target duethus activating pkm2discover pkm2 inhibitorscompounds targeting pkm2present perspective focuseslow catalytic statepkm2 proteintetrameric formationmetabolic dysfunctionlactate productioninterrelated conditionschiefly activebetter efficacyallow atpallosteric siteallosteric regulation