IPN60090 dihydrochloride

• CAT Number: I014833
• CAS Number: 2102101-72-2
• Molecular Formula: C24H29Cl2F3N8O3
• Molecular Weight: 605.44
• Purity: ≥95%
• Synonyms: 1-[(2R)-4-[6-[[2-[4-(3,3-difluorocyclobutyl)oxy-6-methylpyridin-2-yl]acetyl]amino]pyridazin-3-yl]-2-fluorobutyl]-N-methyltriazole-4-carboxamide;dihydrochloride
• InChI: 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
• InChIKey: MREGZVYRKYDENT-QCUBGVIVSA-N
• SMILES: CC1=CC(=CC(=N1)CC(=O)NC2=NN=C(C=C2)CCC(CN3C=C(N=N3)C(=O)NC)F)OC4CC(C4)(F)F.Cl.Cl

IPN-60090 dihydrochloride is an orally active and highly selective inhibitor of glutaminase 1 (GLS1; IC50=31 nM), with no activity observed against GLS-2. IPN-60090 dihydrochloride exhibits excellent physicochemical and pharmacokinetic properties in vivo. IPN-60090 dihydrochloride can be used for solid tumors research, such as lung and ovarian cancers[1][2].
There are two known isoforms of glutaminase: GLS-1 (also called kidney-type or KGA), and GLS-2 (also called liver-type or LGA). GLS-1 is ubiquitous and GLS-2 expression appears limited primarily to the liver.In a dual-coupled enzyme assay, IPN60090 dihydrochloride inhibits purified recombinant human GLS-1 (GAC isoform) with an IC50 of 31 nM, and has no activity against GLS-2, with an IC50 of >50000 nM[2].IPN60090 dihydrochloride inhibits the proliferation of A549 cells with an IC50 of 26 nM[2].
IPN60090 dihydrochloride (3 mg/kg for i.v.; 10 mg/kg for p.o.) has excellent pharmacokinetic properties, with CL=4.1 mL/min/kg, t1/2=1 hour, Cmax=19 μM, F%=89%[2].IPN-60090 dihydrochloride (oral administration; 100 mg/kg; twice daily; 30 days) shows similar efficacy and target engagement to CB-839 (HY-12248) dosed orally at 250 mg/kg twice daily. And the 100 mg/kg BID dose of IPN-60090 is a tolerated dose for the following model study[2].IPN-60090 dihydrochloride (oral administration; 100 mg/kg; twice daily; 30 days; monotherapy or in combination with TAK228 (HY-13328)) causes tumor growth inhibition. IPN-60090 alone demonstrates robust in vivo target engagement in a dose-dependent manner. The glutamate/glutamine ratios and the free plasma concentrations of IPN-60090 at 4 hours post-dose on both day 4 and day 28 are all decreased[2]. Furthermore, IPN-60090 dihydrochloride in combination with TAK228 strongly causes an 85% tumor growth inhibition, IPN-60090 alone causes a 28% tumor growth inhibition in vivo[2].

Reference

[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.
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