TY - JOUR
T1 - 5-Aryl-1,3,4-oxadiazol-2-ylthioalkanoic Acids
T2 - A Highly Potent New Class of Inhibitors of Rho/Myocardin-Related Transcription Factor (MRTF)/Serum Response Factor (SRF)-Mediated Gene Transcription as Potential Antifibrotic Agents for Scleroderma
AU - Kahl, Dylan J.
AU - Hutchings, Kim M.
AU - Lisabeth, Erika Mathes
AU - Haak, Andrew J.
AU - Leipprandt, Jeffrey R.
AU - Dexheimer, Thomas
AU - Khanna, Dinesh
AU - Tsou, Pei Suen
AU - Campbell, Phillip L.
AU - Fox, David A.
AU - Wen, Bo
AU - Sun, Duxin
AU - Bailie, Marc
AU - Neubig, Richard R.
AU - Larsen, Scott D.
N1 - Funding Information:
This research was supported by NIH NIAMS award R01AR066049 (S.D.L.) and NIH NIGMS award R01GM115459-01A1 (R.R.N.). Support was also provided in part by a University of Michigan Mi-TRAC award (S.D.L. and R.R.N.) sponsored by the Michigan Economic Development Corporation.
Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/5/9
Y1 - 2019/5/9
N2 - Through a phenotypic high-throughput screen using a serum response element luciferase promoter, we identified a novel 5-aryl-1,3,4-oxadiazol-2-ylthiopropionic acid lead inhibitor of Rho/myocardin-related transcription factor (MRTF)/serum response factor (SRF)-mediated gene transcription with good potency (IC50 = 180 nM). We were able to rapidly improve the cellular potency by 5 orders of magnitude guided by sharply defined and synergistic SAR. The remarkable potency and depth of the SAR, as well as the relatively low molecular weight of the series, suggests, but does not prove, that binding to the unknown molecular target may be occurring through a covalent mechanism. The series nevertheless has no observable cytotoxicity up to 100 μM. Ensuing pharmacokinetic optimization resulted in the development of two potent and orally bioavailable anti-fibrotic agents that were capable of dose-dependently reducing connective tissue growth factor gene expression in vitro as well as significantly reducing the development of bleomycin-induced dermal fibrosis in mice in vivo.
AB - Through a phenotypic high-throughput screen using a serum response element luciferase promoter, we identified a novel 5-aryl-1,3,4-oxadiazol-2-ylthiopropionic acid lead inhibitor of Rho/myocardin-related transcription factor (MRTF)/serum response factor (SRF)-mediated gene transcription with good potency (IC50 = 180 nM). We were able to rapidly improve the cellular potency by 5 orders of magnitude guided by sharply defined and synergistic SAR. The remarkable potency and depth of the SAR, as well as the relatively low molecular weight of the series, suggests, but does not prove, that binding to the unknown molecular target may be occurring through a covalent mechanism. The series nevertheless has no observable cytotoxicity up to 100 μM. Ensuing pharmacokinetic optimization resulted in the development of two potent and orally bioavailable anti-fibrotic agents that were capable of dose-dependently reducing connective tissue growth factor gene expression in vitro as well as significantly reducing the development of bleomycin-induced dermal fibrosis in mice in vivo.
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U2 - 10.1021/acs.jmedchem.8b01772
DO - 10.1021/acs.jmedchem.8b01772
M3 - Article
C2 - 30951312
AN - SCOPUS:85065106457
SN - 0022-2623
VL - 62
SP - 4350
EP - 4369
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 9
ER -