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Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties.

ABSTRACT: Inhibition of glutaminase-1 (GLS-1) hampers the proliferation of tumor cells reliant on glutamine. Known glutaminase inhibitors have potential limitations, and in vivo exposures are potentially limited due to poor physicochemical properties. We initiated a GLS-1 inhibitor discovery program focused on optimizing physicochemical and pharmacokinetic properties, and have developed a new selective inhibitor, compound 27 (IPN60090), which is currently in phase 1 clinical trials. Compound 27 attains high oral exposures in preclinical species, with strong in vivo target engagement, and should robustly inhibit glutaminase in humans.

SUBMITTER: Soth MJ

PROVIDER: S-EPMC9007139 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties.

Soth Michael J MJ Le Kang K Di Francesco Maria Emilia ME Hamilton Matthew M MM Liu Gang G Burke Jason P JP Carroll Chris L CL Kovacs Jeffrey J JJ Bardenhagen Jennifer P JP Bristow Christopher A CA Cardozo Mario M Czako Barbara B de Stanchina Elisa E Feng Ningping N Garvey Jill R JR Gay Jason P JP Do Mary K Geck MKG Greer Jennifer J Han Michelle M Harris Angela A Herrera Zachary Z Huang Sha S Giuliani Virginia V Jiang Yongying Y Johnson Sarah B SB Johnson Troy A TA Kang Zhijun Z Leonard Paul G PG Liu Zhen Z McAfoos Timothy T Miller Meredith M Morlacchi Pietro P Mullinax Robert A RA Palmer Wylie S WS Pang Jihai J Rogers Norma N Rudin Charles M CM Shepard Hannah E HE Spencer Nakia D ND Theroff Jay J Wu Qi Q Xu Alan A Yau Ju Anne JA Draetta Giulio G Toniatti Carlo C Heffernan Timothy P TP Jones Philip P

Journal of medicinal chemistry 20201029 21

Inhibition of glutaminase-1 (GLS-1) hampers the proliferation of tumor cells reliant on glutamine. Known glutaminase inhibitors have potential limitations, and in vivo exposures are potentially limited due to poor physicochemical properties. We initiated a GLS-1 inhibitor discovery program focused on optimizing physicochemical and pharmacokinetic properties, and have developed a new selective inhibitor, compound <b>27</b> (IPN60090), which is currently in phase 1 clinical trials. Compound <b>27< ...[more]

PMID: 33118821

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Project description:Purpose:To further explore the molecular mechanisms of LCA treatment underlying its tumor suppressive functions. Methods:For the NOZ cells cultures, there were two different conditions performed in biological triplicates: (I) mock (DMSO), (II) 150 μM LCA for 24 h. A total amount of 1 µg RNA per sample was used as input material for the RNA sample preparations. Sequencing libraries were generated using NEBNext® UltraTM RNA Library Prep Kit for Illumina® (NEB, USA) following manufacturer’s recommendations and index codes were added to attribute sequences to each sample. The clustering of the index-coded samples was performed on a cBot Cluster Generation System using TruSeq PE Cluster Kit v3-cBot-HS (Illumina) according to the manufacturer’s instructions. After cluster generation, the library preparations were sequenced on an Illumina Novaseq platform and 150 bp paired-end reads were generated. Paired t-test was used to normalize and statistically analyze the data. The threshold we set to screen for upregulated and downregulated genes with a fold change >0 and a padj-value < 0.05. Hierarchical clustering was performed and a heat map was constructed with edgeR R package (3.18.1) to visualize differential mRNA expression. Gene set enrichment analysis was conducted with the local version of the GSEA analysis tool http://www.broadinstitute.org/gsea/index.jsp. Results: By means of RNA-seq and subsequent data analysis with volcano plot and hierarchical clustering, we found that LCA treatment led to a different gene expression profile with the upregulation of 3607 genes and the downregulation of 3501genes compared with those in cells treated with mock. Gene Set Enrichment Analysis (GSEA) suggested that alanine, aspartate, and glutamate metabolism pathways were top-listed in the inhibitory regulation of LCA, and the heatmap plots showed that the pathways involved a set of 35genes. In addition, qRT-PCR was used to confirm the expression of several metabolism genes including GLS, ASS1, CPS1, ASNS, ABAT, and ADSSL. We were particularly interested in the commonly downregulated GLS in both NOZ and EH-GB1 cells, which mediates glutamate and glutamine metabolism. As the result, protein levels of GLS were dramatically inhibited by LCA in NOZ and EH-GB1 cells in a time-dependent manner as compared with the untreated cancer cells, Conclusion: GLS was a downstream effector of LCA treatment in gallbladder cancer.

Dataset Information

Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties.

Publications

Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties.

Similar Datasets

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