TY - JOUR
T1 - Inactivators of Ornithine Aminotransferase for the Treatment of Hepatocellular Carcinoma
AU - Silverman, Richard B.
N1 - Funding Information:
I am grateful for financial support from the National Institutes of Health (R01 CA260250 and R01 DA030604) and for my outstanding graduate students (GS), postdocs (PD), and collaborators (C) involved in the OAT inactivator project, who all make me look good: Hyunbeom Lee (GS), Jose I. Juncosa (PD), Hoang V. Le (PD), Matthew J. Moschitto (PD), Wei Zhu (PD), Pathum Weerawarna (PD), Sida Shen (PD), Timothy A. Dwight (PD), Hejun Lu (PD), Yaron Ilan (C), Ehud Zigmond (C), Ami Ben Ya’acov (C), Yoav Lichtenstein (C), Zvi Shalev (C), Yoav Smith (C), Lidya Zolotarov (C), Ehud Ziv (C), Rony Kalman (C), Neil L. Kelleher (C), Peter F. Doubleday (C), Rafael D. Melani (C), Zdzislaw Wawrzak (C), Dali Liu (C), Daniel S. Catlin (C), Arseniy Butrin (C), Brett A. Beaupre (C), Noel Kadamandla (C), Peidong Zhao (C), Graham R. Moran (C), Mauricio T. Tavares (C), and Glaucio M. Ferreira (C).
Publisher Copyright:
©
PY - 2022/1/13
Y1 - 2022/1/13
N2 - Hepatocellular carcinoma (HCC) is the second or third leading cause of cancer mortality worldwide (depending on which statistics are used), yet there is no effective treatment. Currently, there are nine FDA-approved drugs for HCC, five monoclonal antibodies and four tyrosine kinase inhibitors. Ornithine aminotransferase (OAT) has been validated as a target in preclinical studies, which demonstrates that it is a potential target to treat HCC. Currently, there are no OAT inactivators in clinical trials for HCC. This Innovation describes evidence to support inhibition of OAT as a novel approach for HCC tumor growth inhibition. After the mechanism of OAT is discussed, the origins of our involvement in OAT inactivation, based on our previous work on mechanism-based inactivation of GABA-AT, are described. Once it was demonstrated that OAT inactivation does lead to HCC tumor growth inhibition, new selective OAT inactivators were designed and their inactivation mechanisms were elucidated. A summary of these mechanistic studies is presented. Inactivators of OAT provide the potential for treatment of HCC, targeting the Wnt/β-catenin pathway.
AB - Hepatocellular carcinoma (HCC) is the second or third leading cause of cancer mortality worldwide (depending on which statistics are used), yet there is no effective treatment. Currently, there are nine FDA-approved drugs for HCC, five monoclonal antibodies and four tyrosine kinase inhibitors. Ornithine aminotransferase (OAT) has been validated as a target in preclinical studies, which demonstrates that it is a potential target to treat HCC. Currently, there are no OAT inactivators in clinical trials for HCC. This Innovation describes evidence to support inhibition of OAT as a novel approach for HCC tumor growth inhibition. After the mechanism of OAT is discussed, the origins of our involvement in OAT inactivation, based on our previous work on mechanism-based inactivation of GABA-AT, are described. Once it was demonstrated that OAT inactivation does lead to HCC tumor growth inhibition, new selective OAT inactivators were designed and their inactivation mechanisms were elucidated. A summary of these mechanistic studies is presented. Inactivators of OAT provide the potential for treatment of HCC, targeting the Wnt/β-catenin pathway.
KW - Hepatocellular carcinoma
KW - Mechanism-based inactivation
KW - Ornithine aminotransferase
KW - Wnt/β-catenin
KW - X-ray crystal structure
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U2 - 10.1021/acsmedchemlett.1c00526
DO - 10.1021/acsmedchemlett.1c00526
M3 - Article
C2 - 35059122
AN - SCOPUS:85121024797
SN - 1948-5875
VL - 13
SP - 38
EP - 49
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 1
ER -
