Design and evaluation of novel analogs of 2-amino-4-boronobutanoic acid (ABBA) as inhibitors of human gamma-glutamyl transpeptidase

Nguyen, Luong; Schultz, Daniel C.; Terzyan, Simon S.; Rezaei, Mohammad; Songb, Jinhua; Li, Chenglong; You, Youngjae; Hanigan, Marie H.

doi:10.1016/j.bmc.2022.116986

Title: Design and evaluation of novel analogs of 2-amino-4-boronobutanoic acid (ABBA) as inhibitors of human gamma-glutamyl transpeptidase

Journal Article · 26 August 2022 · Bioorganic and Medicinal Chemistry

DOI: https://doi.org/10.1016/j.bmc.2022.116986 · OSTI ID:2423896

Nguyen, Luong ^[1];

^[2]; Terzyan, Simon S. ^[3];

^[4]; Songb, Jinhua ^[5]; Li, Chenglong ^[2];

^[6];

^[3]

State Univ. of New York (SUNY), Buffalo, NY (United States); PostEra, San Francisco, CA (United States)
Univ. of Florida, Gainesville, FL (United States)
Univ. of Oklahoma Health Sciences Center, Oklahoma City, OK (United States)
Univ. of Florida, Gainesville, FL (United States); Scorpion Therapeutics, Boston, MA (United States)
Univ. of Florida, Gainesville, FL (United States); AAT Bioquest, Inc., Sunnyvale, CA (United States)
State Univ. of New York (SUNY), Buffalo, NY (United States)

Inhibitors of gamma-glutamyl transpeptidase (GGT1, aka gamma-glutamyl transferase) are needed for the treatment of cancer, cardiovascular illness and other diseases. Compounds that inhibit GGT1 have been evaluated in the clinic, but no inhibitor has successfully demonstrated specific and systemic GGT1 inhibition. All have severe side effects. L-2-amino-4-boronobutanoic acid (l-ABBA), a glutamate analog, is the most potent GGT1 inhibitor in vitro. In this study, we have solved the crystal structure of human GGT1 (hGGT1) with ABBA bound in the active site. The structure was interrogated to identify interactions between the enzyme and the inhibitor. Based on these data, a series of novel ABBA analogs were designed and synthesized. Their inhibitory activity against the hydrolysis and transpeptidation activities of hGGT1 were determined. The lead compounds were crystalized with hGGT1 and the structures solved. The kinetic data and structures of the complexes provide new insights into the critical role of protein structure dynamics in developing compounds for inhibition of hGGT1.

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Research Organization:: SLAC National Accelerator Laboratory, Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-76SF00515; SC0012704

OSTI ID:: 2423896

Journal Information:: Bioorganic and Medicinal Chemistry, Journal Name: Bioorganic and Medicinal Chemistry Journal Issue: C Vol. 73; ISSN 0968-0896

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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Title: Design and evaluation of novel analogs of 2-amino-4-boronobutanoic acid (ABBA) as inhibitors of human gamma-glutamyl transpeptidase

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