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

Soth, Michael; Kang, Le; Francesco, Maria Emilia Di; Hamilton, Matthew M.; Liu, Gang; Burke, Jason P.; Carroll, Chris L; Kovacs, Jeffery; Bardenhagen, Jennifer; Bristow, Christopher A.; Cardozo, Mario; Czakó, Barbara; Stanchina, Elisa de; Feng, Ningping; Garvey, Jill R; Geck, Mary; Greer, Jennifer; Han, Michelle; Harris, Angela L.; Herrera, Zachary; Huang, Sha; Giuliani, Virginia; Jiang, Yongying; Johnson, Sarah; Johnson, Troy A.; Kang, Zhijun; Leonard, Paul G.; Liu, Zhen; McAfoos, Timothy; Miller, Meredith A.; Morlacchi, Pietro; Mullinax, Robert A.; Palmer, Wylie S.; Pang, Jihai; Rogers, Norma; Rudin, Charles M.; Shepard, Hannah E.; Spencer, Nakia D.; Theroff, Jay; Qi, Weimin; Xu, Alan; Yau, Ju Anne; Draetta, Giulio; Toniatti, Carlo; Heffernan, Timothy P.; Jones, Philip

doi:10.1021/acs.jmedchem.0c01398

Cited by 56 publications

(38 citation statements)

References 37 publications

(78 reference statements)

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“…Drugs targeting glutaminase, such as CB-839 and IPN60090, have been effective in some preclinical models and are now in trials for various malignancies. [120][121][122]167 Interestingly, targeting glutaminase appears to cooperate in preclinical settings with immune therapies, including chimeric antigen receptor T-cell therapies. 168 In addition, for several glutamine transporters, such as SLC1A5, LAT1, and SLC6A14, inhibition showed promising results in preclinical settings and are being actively pursued for future clinical applications.…”

Section: Cancer Cell Metabolismmentioning

confidence: 99%

“…In this section we provide select examples of the major classes of cancer drugs that target metabolic enzymes (Table 1). 97‐143 For a more comprehensive discussion, the reader is referred to other excellent reviews of this topic 4,144‐146 …”

Section: Metabolism In Tumors and Patients With Cancermentioning

confidence: 99%

“…One route of glutamine catabolism to supply carbon to cells involves the enzyme glutaminase. Drugs targeting glutaminase, such as CB‐839 and IPN60090, have been effective in some preclinical models and are now in trials for various malignancies 120‐122,167 . Interestingly, targeting glutaminase appears to cooperate in preclinical settings with immune therapies, including chimeric antigen receptor T‐cell therapies 168 .…”

Section: Metabolism In Tumors and Patients With Cancermentioning

confidence: 99%

See 2 more Smart Citations

Metabolomics in cancer research and emerging applications in clinical oncology

Schmidt

Patel

Kirsch

et al. 2021

CA A Cancer J Clinicians

363

271

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Cancer has myriad effects on metabolism that include both rewiring of intracellular metabolism to enable cancer cells to proliferate inappropriately and adapt to the tumor microenvironment, and changes in normal tissue metabolism. With the recognition that fluorodeoxyglucose-positron emission tomography imaging is an important tool for the management of many cancers, other metabolites in biological samples have been in the spotlight for cancer diagnosis, monitoring, and therapy. Metabolomics is the global analysis of small molecule metabolites that like other -omics technologies can provide critical information about the cancer state that are otherwise not apparent. Here, the authors review how cancer and cancer therapies interact with metabolism at the cellular and systemic levels. An overview of metabolomics is provided with a focus on currently available technologies and how they have been applied in the clinical and translational research setting. The authors also discuss how metabolomics could be further leveraged in the future to improve the management of patients with cancer.

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Section: Cancer Cell Metabolismmentioning

confidence: 99%

Section: Metabolism In Tumors and Patients With Cancermentioning

confidence: 99%

Section: Metabolism In Tumors and Patients With Cancermentioning

confidence: 99%

See 1 more Smart Citation

Metabolomics in cancer research and emerging applications in clinical oncology

Schmidt

Patel

Kirsch

et al. 2021

CA A Cancer J Clinicians

363

271

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“…Notably, a positive feedback loop between GLS1 and β-catenin exists, highlighting a mutual regulation of these two players contributing to the maintenance and expansion of the CSC population [ 23 ]. GLS1 targeting is of particular interest in cancer, and GLS1 inhibitors are being evaluated in clinical trials in patients with leukemia and solid tumors [ 24 ].…”

Section: Molecular Pathways Regulating Cscs In Hccmentioning

confidence: 99%

Hepatic Cancer Stem Cells: Molecular Mechanisms, Therapeutic Implications, and Circulating Biomarkers

Gramantieri

Giovannini

Suzzi

et al. 2021

Cancers

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Hepatocellular carcinoma (HCC) is one of the deadliest cancers. HCC is associated with multiple risk factors and is characterized by a marked tumor heterogeneity that makes its molecular classification difficult to apply in the clinics. The lack of circulating biomarkers for the diagnosis, prognosis, and prediction of response to treatments further undermines the possibility of developing personalized therapies. Accumulating evidence affirms the involvement of cancer stem cells (CSCs) in tumor heterogeneity, recurrence, and drug resistance. Owing to the contribution of CSCs to treatment failure, there is an urgent need to develop novel therapeutic strategies targeting, not only the tumor bulk, but also the CSC subpopulation. Clarification of the molecular mechanisms influencing CSC properties, and the identification of their functional roles in tumor progression, may facilitate the discovery of novel CSC-based therapeutic targets to be used alone, or in combination with current anticancer agents, for the treatment of HCC. Here, we review the driving forces behind the regulation of liver CSCs and their therapeutic implications. Additionally, we provide data on their possible exploitation as prognostic and predictive biomarkers in patients with HCC.

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“…Gross et al, 2014; William P Katt et al, 2017). Both CB-839 and a more recently described compound, IPN60090, have advanced to clinical trials (Harding et al, 2015; Soth et al, 2020), although CB-839 has not been approved as yet as an anti-cancer drug, while IPN60090 has reportedly been removed from trials entirely (AdisInsight, 2021). Despite the extensive optimization efforts conducted during its discovery, CB-839 has both a higher calculated logP (ClogP, a measure of lipophilicity) and lower lipophilic efficiency (LipE, a measure of inhibitory potency relative to lipophilicity) than BPTES (L.…”

Section: Introductionmentioning

confidence: 99%

New Insights into the Mechanisms Used by Inhibitors Targeting Glutamine Metabolism in Cancer Cells

Milano

Huang

Nguyen

et al. 2021

Preprint

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Many cancer cells become dependent on glutamine metabolism to compensate for glycolysis being uncoupled from the TCA cycle. The mitochondrial enzyme Glutaminase C (GAC) satisfies this "glutamine addiction" by catalyzing the first step in glutamine metabolism, making it an attractive drug target. Despite one of the allosteric inhibitors (CB-839) being in clinical trials, none of the drugs targeting GAC are approved for cancer treatment and their mechanism of action is not well understood. A major challenge has been the rational design of better drug candidates: standard cryo-cooled X-ray crystal structures of GAC bound to CB-839 and its analogs fail to explain their potency differences. Here, we address this problem by using an emerging technique, serial room temperature crystallography, which enabled us to observe clear differences between the binding conformations of inhibitors with significantly different potencies. A computational model was developed to further elucidate the molecular basis of inhibitor potency. We then corroborated the results from our modeling efforts by using recently established fluorescence assays that directly read-out inhibitor binding to GAC. Together, these findings provide new insights into the mechanisms used by a major class of allosteric GAC inhibitors and for the future rational design of more potent drug candidates.

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

Cited by 56 publications

References 37 publications

Metabolomics in cancer research and emerging applications in clinical oncology

Metabolomics in cancer research and emerging applications in clinical oncology

Hepatic Cancer Stem Cells: Molecular Mechanisms, Therapeutic Implications, and Circulating Biomarkers

New Insights into the Mechanisms Used by Inhibitors Targeting Glutamine Metabolism in Cancer Cells

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