GS-444217 | CAS# 1262041-49-5 | ASK1 Inhibitor

MedKoo Cat#: 564706 | Name: GS-444217

Description:

WARNING: This product is for research use only, not for human or veterinary use.

GS-444217, also known as ASK1-IN-1, is a potent and selective inhibitor of apoptosis signal-regulating kinase 1 (ASK1). In SD rats, GS-444217 prevented proteinuria and glomerular thrombosis with suppression of macrophage activation on day 1 NTN. In WKY rats, GS-444217 reduced crescent formation, prevented renal impairment and reduced proteinuria on day 14 NTN. Macrophage activation, T-cell infiltration and renal fibrosis were also reduced by GS-444217. I

Chemical Structure

GS-444217

CAS#1262041-49-5

Theoretical Analysis

MedKoo Cat#: 564706

Name: GS-444217

CAS#: 1262041-49-5

Chemical Formula: C23H21N7O

Exact Mass: 411.1808

Molecular Weight: 411.47

Elemental Analysis: C, 67.14; H, 5.14; N, 23.83; O, 3.89

Price and Availability

Size	Price	Availability
5mg	USD 90.00	Ready to ship
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship
200mg	USD 1,350.00	Ready to ship
500mg	USD 2,850.00	Ready to ship

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Related CAS #

No Data

Synonym

GS444217; GS 444217; GS-444217; ASK1-IN-1; ASK1-IN 1; ASK1-IN1;

IUPAC/Chemical Name

4-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(3-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)phenyl)picolinamide

InChi Key

ZGCMQKWOUIMBEP-UHFFFAOYSA-N

InChi Code

InChI=1S/C23H21N7O/c31-23(20-11-19(8-9-24-20)29-12-21(25-13-29)15-4-5-15)27-17-3-1-2-16(10-17)22-28-26-14-30(22)18-6-7-18/h1-3,8-15,18H,4-7H2,(H,27,31)

SMILES Code

O=C(NC1=CC=CC(C2=NN=CN2C3CC3)=C1)C4=NC=CC(N5C=C(C6CC6)N=C5)=C4

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO

Shelf Life

>3 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#A9T09K24

QC Data

View QC data: current batch, Lot#A9T09K24

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

GS-444217 is an inhibitor of apoptosis signal-regulating kinase 1 (ASK1) with an IC50 of 2.87 nM.

In vitro activity:

The effect of GS-444217 to inhibit ASK1 autophosphorylation and ASK1-mediated signaling was evaluated in cell-based assays. Treatment with GS-444217 reduced ASK1 phosphorylation and prevented the phosphorylation of MKK3/6, MKK4, p38, and JNK at concentrations of 0.3 μM and above with full suppression of ASK1 activity at 1 μM. GS-444217 reduced ASK1 activity within 5 minutes of addition to the cultures, reaching a maximum level of inhibition by 30 minutes (Figure 3B). Removal of GS-444217 from the cultures resulted in reactivation of ASK1 autophosphorylation within 10 minutes and near-complete recovery 2 hours after drug washout (Figure 3C). Reference: J Clin Invest. 2018 Oct 1;128(10):4485-4500. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159961/

In vivo activity:

The efficacy of GS-444217 to reduce ASK1-mediated kinase activation, tubular epithelial cell death, interstitial inflammation, and fibrosis in kidney was tested in a 7-day UUO (unilateral ureteral obstruction) model in rats (Supplemental Figure 5C). In comparison with rats without UUO, p-p38 and p-JNK levels were elevated in obstructed kidneys and were reduced by GS-444217 orally administered at 30 mg/kg twice per day (Figure 5, E–G). Activation of ASK1 during UUO was reduced by oral administration of GS-444217 (Supplemental Figure 9A). UUO caused increases in markers of fibrosis such as collagen IV deposition (Figure 5, H–K), collagen I (Col1a1) mRNA expression (Figure 5L), total collagen (Supplemental Figure 9C), cortical interstitial α-smooth muscle actin–positive (α-SMA–positive) myofibroblasts (Figure 5M), tubular epithelial cell death (TUNEL-positive cells) (Figure 5N and Supplemental Figure 9B), and positive staining with Masson’s trichrome (Supplemental Figure 9D). Treatment of UUO rats with GS-444217 reduced these measures of tubular injury and fibrosis and associated expression of profibrotic genes (e.g., connective tissue growth factor [Ctgf], plasminogen activator inhibitor [Serpine1], and Tgfb1) (Supplemental Figure 10, C–E). Reference: J Clin Invest. 2018 Oct 1;128(10):4485-4500. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159961/

	Solvent	mg/mL	mM
Solubility
	DMSO	37.8	91.74

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 411.47 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Liles JT, Corkey BK, Notte GT, Budas GR, Lansdon EB, Hinojosa-Kirschenbaum F, Badal SS, Lee M, Schultz BE, Wise S, Pendem S, Graupe M, Castonguay L, Koch KA, Wong MH, Papalia GA, French DM, Sullivan T, Huntzicker EG, Ma FY, Nikolic-Paterson DJ, Altuhaifi T, Yang H, Fogo AB, Breckenridge DG. ASK1 contributes to fibrosis and dysfunction in models of kidney disease. J Clin Invest. 2018 Oct 1;128(10):4485-4500. doi: 10.1172/JCI99768. Epub 2018 Jul 19. PMID: 30024858; PMCID: PMC6159961. 2. Budas GR, Boehm M, Kojonazarov B, Viswanathan G, Tian X, Veeroju S, Novoyatleva T, Grimminger F, Hinojosa-Kirschenbaum F, Ghofrani HA, Weissmann N, Seeger W, Liles JT, Schermuly RT. ASK1 Inhibition Halts Disease Progression in Preclinical Models of Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2018 Feb 1;197(3):373-385. doi: 10.1164/rccm.201703-0502OC. PMID: 28910144.

In vitro protocol:

In vivo protocol:

1: Ding J, Cui S, Li SY, Cui LY, Nan QY, Lin XJ, Xuan MY, Jin J, Piao SG, Jiang YJ, Zheng HL, Jin JZ, Chung BH, Yang CW, Cui JH, Li C. The angiotensin receptor neprilysin inhibitor LCZ696 attenuates renal fibrosis via ASK1/JNK/p38 MAPK- mediated apoptosis in unilateral ureteral obstruction. PLoS One. 2023 Jun 13;18(6):e0286903. doi: 10.1371/journal.pone.0286903. PMID: 37310976; PMCID: PMC10263316. 2: Qin J, Cao M, Hu X, Tan W, Ma B, Cao Y, Chen Z, Li Q, Hu G. Dual inhibitors of ASK1 and PDK1 kinases: Design, synthesis, molecular docking and mechanism studies of N-benzyl pyridine-2-one containing derivatives as anti-fibrotic agents. Eur J Med Chem. 2023 Feb 5;247:115057. doi: 10.1016/j.ejmech.2022.115057. Epub 2022 Dec 30. PMID: 36603508. 3: Ogier JM, Gao Y, Dunne EM, Wilson MA, Ranganathan SC, Tesch GH, Nikolic Paterson DJ, Dabdoub A, Burt RA, Nayagam BA, Lockhart PJ. ASK1 is a novel molecular target for preventing aminoglycoside-induced hair cell death. J Mol Med (Berl). 2022 May;100(5):797-813. doi: 10.1007/s00109-022-02188-1. Epub 2022 Apr 26. Erratum in: J Mol Med (Berl). 2022 May 10;: PMID: 35471608; PMCID: PMC9110505. 4: Jin L, Kom MC, Fu G, Xie Y, Gao Y, Shen J, Huang H, Hu B, Yan J. Hexavalent chromium induces hepatocyte apoptosis via regulation of apoptosis signal- regulating kinase 1/c-Jun amino-terminal kinase signaling. Environ Toxicol. 2022 Jun;37(6):1288-1296. doi: 10.1002/tox.23483. Epub 2022 Feb 15. PMID: 35166444. 5: Chen A, Xu J, Lai H, D'Agati VD, Guan TJ, Badal S, Liles J, He JC, Lee K. Inhibition of apoptosis signal-regulating kinase 1 mitigates the pathogenesis of human immunodeficiency virus-associated nephropathy. Nephrol Dial Transplant. 2021 Feb 20;36(3):430-441. doi: 10.1093/ndt/gfaa198. PMID: 33097961; PMCID: PMC7898019. 6: McNair AJ, Wilson KS, Martin PE, Welsh DJ, Dempsie Y. Connexin 43 plays a role in proliferation and migration of pulmonary arterial fibroblasts in response to hypoxia. Pulm Circ. 2020 Jul 6;10(3):2045894020937134. doi: 10.1177/2045894020937134. PMID: 32670564; PMCID: PMC7338651. 7: Schuster-Gaul S, Geisler LJ, McGeough MD, Johnson CD, Zagorska A, Li L, Wree A, Barry V, Mikaelian I, Jih LJ, Papouchado BG, Budas G, Hoffman HM, Feldstein AE. ASK1 inhibition reduces cell death and hepatic fibrosis in an Nlrp3 mutant liver injury model. JCI Insight. 2020 Jan 30;5(2):e123294. doi: 10.1172/jci.insight.123294. PMID: 31996485; PMCID: PMC7098717. 8: Liles JT, Corkey BK, Notte GT, Budas GR, Lansdon EB, Hinojosa-Kirschenbaum F, Badal SS, Lee M, Schultz BE, Wise S, Pendem S, Graupe M, Castonguay L, Koch KA, Wong MH, Papalia GA, French DM, Sullivan T, Huntzicker EG, Ma FY, Nikolic- Paterson DJ, Altuhaifi T, Yang H, Fogo AB, Breckenridge DG. ASK1 contributes to fibrosis and dysfunction in models of kidney disease. J Clin Invest. 2018 Oct 1;128(10):4485-4500. doi: 10.1172/JCI99768. Epub 2018 Jul 19. PMID: 30024858; PMCID: PMC6159961. 9: Amos LA, Ma FY, Tesch GH, Liles JT, Breckenridge DG, Nikolic-Paterson DJ, Han Y. ASK1 inhibitor treatment suppresses p38/JNK signalling with reduced kidney inflammation and fibrosis in rat crescentic glomerulonephritis. J Cell Mol Med. 2018 Sep;22(9):4522-4533. doi: 10.1111/jcmm.13705. Epub 2018 Jul 11. PMID: 29998485; PMCID: PMC6111820. 10: Budas GR, Boehm M, Kojonazarov B, Viswanathan G, Tian X, Veeroju S, Novoyatleva T, Grimminger F, Hinojosa-Kirschenbaum F, Ghofrani HA, Weissmann N, Seeger W, Liles JT, Schermuly RT. ASK1 Inhibition Halts Disease Progression in Preclinical Models of Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2018 Feb 1;197(3):373-385. doi: 10.1164/rccm.201703-0502OC. PMID: 28910144. 11: Tesch GH, Ma FY, Han Y, Liles JT, Breckenridge DG, Nikolic-Paterson DJ. ASK1 Inhibitor Halts Progression of Diabetic Nephropathy in Nos3-Deficient Mice. Diabetes. 2015 Nov;64(11):3903-13. doi: 10.2337/db15-0384. Epub 2015 Jul 15. PMID: 26180085.