Novel allosteric glutaminase inhibitors with macrocyclic structure activity relationship analysis (part 2)

Glutamine‐addicted cancer metabolism is recently recognized as novel cancer target especially for KRAS and KEAP1 co‐occurring mutations. To identify more drug‐like GLS inhibitors, we report the amides in the wing macrocycles for GLS inhibition with unique SAR analysis. Although the amidotriazoles (a...

Full description

Saved in:

Bibliographic Details
Published in:	Bulletin of the Korean Chemical Society Vol. 45; no. 7; pp. 639 - 644
Main Authors:	Lee, Eun Ji, Jang, Jiyoon, Cyriac, Rajath, Yun, Mi Ran, Kwon, Yeongju, Jung, Myoung Eun, Choi, Gildon, Chae, Chong Hak, Cho, Byoung Chul, Lee, Kwangho
Format:	Journal Article
Language:	English
Published:	Weinheim Wiley‐VCH Verlag GmbH & Co. KGaA 01-07-2024 대한화학회
Subjects:	anticancer BPTES cancer metabolism GLS glutaminase KEAP1 KRAS macrocycle 화학
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Glutamine‐addicted cancer metabolism is recently recognized as novel cancer target especially for KRAS and KEAP1 co‐occurring mutations. To identify more drug‐like GLS inhibitors, we report the amides in the wing macrocycles for GLS inhibition with unique SAR analysis. Although the amidotriazoles (amides in the wing) are in general less potent than those of acylaminothiadiazole analogs (reverse amides in the wing), macrocycle 4, 5, and 7 are selected as a potent macrocyclic GLS inhibitor in both biochemical and cell viability assays. Selected molecules result in partial reduction in intracellular glutamate levels in LR (LDK378‐resistant) cells which is consistent to their cells viability result. Finally, selected compounds reduce the growth of A549 and H460 cells which have co‐occurring mutations including KRAS and KEAP1. The putative binding mode of macrocycle 4 is also suggested using a molecular docking model. Medicinal chemistry strategy and binding pose of novel macrocyclic glutaminase inhibitor 4 in the allosteric site of glutaminase.
Bibliography:	Eun Ji Lee, Jiyoon Jang, Rajath Cyriac, and Mi Ran Yun contributed equally to this work.
ISSN:	1229-5949 0253-2964 1229-5949
DOI:	10.1002/bkcs.12883