A Phase I, Open Label, Dose Escalation and Dose Expansion Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Anti-tumour Activity of IPN60090 as Single Agent and in Combination in Patients With Advanced Solid Tumours

The purpose of the protocol is to determine safety, tolerability, recommended dose (RD), pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumour activity of IPN60090 as a single agent (Part A) and in combination with pembrolizumab (Part B) or paclitaxel (Part C) in patients with advanced solid tumours and to evaluate food effect (Part D).

Start Date22 Mar 2019

Sponsor / Collaborator

Ipsen SA

100 Clinical Results associated with IPN60090

100 Translational Medicine associated with IPN60090

100 Patents (Medical) associated with IPN60090

Literatures (Medical) associated with IPN60090

19 Sep 2024·Cancer Biomarkers

Glutaminase 1 plays critical roles in myelodysplastic syndrome and acute myeloid leukemia cells

Article

Author: Okabe*, Seiichi ; Gotoh, Akihiko ; Moriyama, Mitsuru ; Arai, Yuya ; Okabe Seiichi

BACKGROUND: Myelodysplastic syndrome (MDS) features bone marrow failure and a heightened risk of evolving into acute myeloid leukemia (AML), increasing with age and reducing overall survival. Given the unfavorable outcomes of MDS, alternative treatments are necessary. Glutamine, the most abundant amino acid in the blood, is metabolized first by the enzyme glutaminase (GLS). OBJECTIVES: To investigate whether GLS is involved in the progression of MDS. The efficacy of GLS inhibitors (CB839 or IPN60090) and BCL2 inhibitor venetoclax was also examined. METHODS: We employed GLS inhibitors (CB839, IPN60090) and the BCL2 inhibitor venetoclax, prepared as detailed. MDS and AML cell lines were cultured under standard and modified (hypoxic, glutamine-free) conditions. Viability, proliferation, and caspase activity were assessed with commercial kits. RT-PCR quantified gene expression post-shRNA transfection. Mitochondrial potential, ATP levels, proteasome activity, and metabolic functions were evaluated using specific assays. Statistical analyses (t-tests, ANOVA) validated the findings. RESULTS: The glutamine-free medium inhibited the growth of MDS cells. GLS1 expression was higher in AML cells than in normal control samples (GSE15061), whereas GLS2 expression was not. Treatment of MDS and AML cells for 72 h was inhibited in a dose-dependent manner by GLS inhibitors. Co-treatment with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax and GLS inhibitors increased potency. Cells transfected with GLS1 short hairpin RNA showed suppressed proliferation under hypoxic conditions and increased sensitivity to venetoclax. CONCLUSIONS: Targeting glutaminolysis and BCL2 inhibition enhances the therapeutic efficacy and has been proposed as a novel strategy for treating high-risk MDS and AML.

02 Jan 2023·Expert Opinion on Therapeutic Patents

An updated patent review of glutaminase inhibitors (2019–2022)

Review

Author: Huang, Huidan ; Chen, Rui ; Wang, Danni ; Li, Zhiyu ; Bian, Jinlei ; Lu, Yulong ; Gong, Guangyue ; Guo, Ziming ; Li, Xiaohong

INTRODUCTIONKidney-type glutaminase (GLS1), a key enzyme controlling the hydrolysis of glutamine to glutamate to resolve the 'glutamine addiction' of cancer cells, has been shown to play a central role in supporting cancer growth and proliferation. Therefore, the inhibition of GLS1 as a novel cancer treating strategy is of great interest.AREAS COVEREDThis review covers recent patents (2019-present) involving GLS1 inhibitors, which are mostly focused on their chemical structures, molecular mechanisms of action, pharmacokinetic properties, and potential clinical applications.EXPERT OPINIONCurrently, despite significant efforts, the search for potent GLS1 inhibitors has not resulted in the development of compounds for therapeutic applications. Most recent patents and literature focus on GLS1 inhibitors IPN60090 and DRP104, which have entered clinical trials. While other patent disclosures during this period have not generated any drug candidates, the clinical update will inform the potential of these inhibitors as promising therapeutic agents either as single or as combination interventions.

12 Nov 2020·Journal of Medicinal ChemistryQ1 · MEDICINE

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

Q1 · MEDICINE

Article

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

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.

100 Deals associated with IPN60090

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Malignant Solid Neoplasm	Phase 1	US	Ipsen SA	22 Mar 2019
Non-Small Cell Lung Cancer	Phase 1	US	Anderson University	-
Ovarian Cancer	Phase 1	US	Anderson University	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03894540 (CTgov)	Phase 1	Advanced Malignant Solid Neoplasm	22	IPN60090 (IPN60090 20 mg)	djrwpdwjeg(tcvpzengjh) = zefinpfnlj gvsblkpgrm (vgeopsxrbp, hsctsubzia - wuyoevdles) View more	-	22 Nov 2021
				IPN60090 (IPN60090 40 mg)	djrwpdwjeg(tcvpzengjh) = bjsgxgnays gvsblkpgrm (vgeopsxrbp, qaghezgfwn - disosztyrp) View more

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