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IPN-60090 DiHCl (IACS-6274; IACS6274; IPN60090), the dihydrochloride salt of IPN 60090, is a novel, potent, orally bioavailable and selective inhibitor of GLS1 (the kidney-type glutaminase) with potential anticancer and immunostimulating/immunomodulating activities.
| ln Vitro |
GLS-1, also known as kidney type or KGA, and GLS-2, commonly known as hepatic type or LGA, are the two subtypes of glutaminase that are now recognized. Whereas GLS-2 expression seems to be mostly limited to the liver, GLS-1 expression is found everywhere. IPN60090 diHClide is inert against GLS-2 with an IC50 > 50000 nM and inhibits pure recombinant human GLS-1 (GAC isoform) with an IC50 of 31 nM in a dual-coupling enzyme assay [2]. A549 cell growth is inhibited by IPN60090 diHClide at an IC50 of 26 nM[2].
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| ln Vivo |
IPN60090 dihydrochloride (3 mg/kg intravenously; 10 mg/kg orally) is prescribed, with excellent pharmacokinetic features (CL=4.1 mL/min/kg, t1/2=1 hour, Cmax=19 μM, F%=89%)[2]. For 30 days, oral administration of 100 mg/kg of IPN-60090 dihydrochloride twice a day showed comparable efficacy and target engagement to 250 mg/kg of CB-839 twice a day. In later model investigations, the tolerable dose of IPN-60090 was shown to be 100 mg/kg BID [2]. Tumor growth suppression was found with IPN-60090 dihydrochloride (oral; 100 mg/kg; twice daily; 30 days; monotherapy or in combination with TAK228). Significant in vivo target engagement was shown by IPN-60090 alone, and this effect was dose-dependent. Days 4 and 28, four hours after dosage, saw a decrease in the glutamate/glutamine ratio and the free plasma levels of IPN-60090 [2]. Moreover, IPN-60090 dihydrochloride by itself and in conjunction with TAK228 significantly reduced tumor development in vivo by 85% and 28%, respectively [2].
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| Animal Protocol |
Animal/Disease Models: Female CD-1 mice [2]
Doses: 3 mg/kg, intravenous (iv) (iv)injection; 10 mg/kg orally (pharmacokinetic/PK/PK analysis) Route of Administration: intravenous (iv) (iv)injection and oral administration Experimental Results: CL (4.1 mL/min /kg), intravenous (iv) (iv)injection t1/2 (1 hour); PO Cmax (19 μM), F% (89%). Animal/Disease Models: Ru337 non-small cell lung cancer patient-derived xenograft (PDX) subcutaneousmouse model, as monotherapy or combination therapy [2] Doses: 100 mg/kg Route of Administration: po (po (oral gavage)) Route of Administration: po (po (oral gavage)) po (po (oral gavage)) oral. 100 mg/kg; twice (two times) daily; 30 days; monotherapy or in combination with TAK228 Experimental Results: The combination therapy group demonstrated improvement over either agent alone. |
| References |
[1]. Maria Emilia Di Francesco, et al. Gls1 inhibitors for treating disease. WO2016004404A2.
[2]. Michael J Soth, et al. Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties. J Med Chem. 2020 Nov 12;63(21):12957-12977. |
| Molecular Formula |
C24H29CL2F3N8O3
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|---|---|
| Molecular Weight |
605.4442
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| Exact Mass |
532.2158
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| CAS # |
2102101-72-2
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| Related CAS # |
IPN60090;1853164-83-6
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| SMILES |
O=C(C1=CN(C[C@H](F)CCC2=NN=C(NC(CC3=NC(C)=CC(OC4CC(F)(F)C4)=C3)=O)C=C2)N=N1)NC.[H]Cl.[H]Cl
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| InChi Key |
MREGZVYRKYDENT-QCUBGVIVSA-N
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| InChi Code |
InChI=1S/C24H27F3N8O3.2ClH/c1-14-7-18(38-19-10-24(26,27)11-19)8-17(29-14)9-22(36)30-21-6-5-16(31-33-21)4-3-15(25)12-35-13-20(32-34-35)23(37)28-2/h5-8,13,15,19H,3-4,9-12H2,1-2H3,(H,28,37)(H,30,33,36)2*1H/t15-/m1../s1
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| Chemical Name |
(R)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide
dihydrochloride
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| Synonyms |
IPN-60090 IACS-6274 dihydrochlorideIPN 60090 IACS-6274 diHCl IPN60090 IACS6274 IACS 6274
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~170 mg/mL (~280.79 mM)
H2O : ~100 mg/mL (~165.17 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (8.26 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 5 mg/mL (8.26 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 5 mg/mL (8.26 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 50 mg/mL (82.58 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6517 mL | 8.2585 mL | 16.5169 mL | |
| 5 mM | 0.3303 mL | 1.6517 mL | 3.3034 mL | |
| 10 mM | 0.1652 mL | 0.8258 mL | 1.6517 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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