TY - JOUR
T1 - Discovery of Cell-Permeable Allosteric Inhibitors of Liver Pyruvate Kinase
T2 - Design and Synthesis of Sulfone-Based Urolithins
AU - Iqbal, Shazia
AU - Islam, Md Zahidul
AU - Ashraf, Sajda
AU - Kim, Woonghee
AU - AL-Sharabi, Amal A.
AU - Ozcan, Mehmet
AU - Hanashalshahaby, Essam
AU - Zhang, Cheng
AU - Uhlén, Mathias
AU - Boren, Jan
AU - Turkez, Hasan
AU - Mardinoglu, Adil
N1 - Publisher Copyright:
© 2024 by the authors.
PY - 2024/7/22
Y1 - 2024/7/22
N2 - Metabolic dysfunction-associated fatty liver disease (MAFLD) presents a significant global health challenge, characterized by the accumulation of liver fat and impacting a considerable portion of the worldwide population. Despite its widespread occurrence, effective treatments for MAFLD are limited. The liver-specific isoform of pyruvate kinase (PKL) has been identified as a promising target for developing MAFLD therapies. Urolithin C, an allosteric inhibitor of PKL, has shown potential in preliminary studies. Expanding upon this groundwork, our study delved into delineating the structure-activity relationship of urolithin C via the synthesis of sulfone-based urolithin analogs. Our results highlight that incorporating a sulfone moiety leads to substantial PKL inhibition, with additional catechol moieties further enhancing this effect. Despite modest improvements in liver cell lines, there was a significant increase in inhibition observed in HepG2 cell lysates. Specifically, compounds 15d, 9d, 15e, 18a, 12d, and 15a displayed promising IC50 values ranging from 4.3 µM to 18.7 µM. Notably, compound 15e not only demonstrated a decrease in PKL activity and triacylglycerol (TAG) content but also showed efficient cellular uptake. These findings position compound 15e as a promising candidate for pharmacological MAFLD treatment, warranting further research and studies.
AB - Metabolic dysfunction-associated fatty liver disease (MAFLD) presents a significant global health challenge, characterized by the accumulation of liver fat and impacting a considerable portion of the worldwide population. Despite its widespread occurrence, effective treatments for MAFLD are limited. The liver-specific isoform of pyruvate kinase (PKL) has been identified as a promising target for developing MAFLD therapies. Urolithin C, an allosteric inhibitor of PKL, has shown potential in preliminary studies. Expanding upon this groundwork, our study delved into delineating the structure-activity relationship of urolithin C via the synthesis of sulfone-based urolithin analogs. Our results highlight that incorporating a sulfone moiety leads to substantial PKL inhibition, with additional catechol moieties further enhancing this effect. Despite modest improvements in liver cell lines, there was a significant increase in inhibition observed in HepG2 cell lysates. Specifically, compounds 15d, 9d, 15e, 18a, 12d, and 15a displayed promising IC50 values ranging from 4.3 µM to 18.7 µM. Notably, compound 15e not only demonstrated a decrease in PKL activity and triacylglycerol (TAG) content but also showed efficient cellular uptake. These findings position compound 15e as a promising candidate for pharmacological MAFLD treatment, warranting further research and studies.
KW - allosteric PKL inhibition
KW - cell permeability
KW - MAFLD
KW - pyruvate kinase liver
KW - sulfone-based urolithin analogues
KW - TAG content
UR - http://www.scopus.com/inward/record.url?scp=85199777848&partnerID=8YFLogxK
U2 - 10.3390/ijms25147986
DO - 10.3390/ijms25147986
M3 - Article
C2 - 39063228
AN - SCOPUS:85199777848
SN - 1661-6596
VL - 25
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 14
M1 - 7986
ER -