RIPK1 (receptor-interacting protein kinase 1) (IC50 <1 µM)

Eclitasertib (DNL758; SAR443122) is a receptor-interacting serine/ threonine protein (RIP-1) kinase inhibitor that disrupts RIPK1-mediated signaling, and may attenuate inflammation and the resulting tissue damage. RIPK1 is a signaling protein in the tumor necrosis factor (TNF) receptor pathway, playing a key role in inflammation and cell death in response to tissue damage and pathogen recognition [1].

Geometric mean ratio (point estimate [90% confidence interval]) of the relative change from baseline in C-reactive protein with eclitasertib vs. placebo on Day 7 was 0.85 (0.49-1.45; p = 0.30). Median time to 50% decrease in C-reactive protein from baseline was 3 days vs. 5 days (p = 0.056) with eclitasertib vs. placebo. Median time to ≥ 2-point improvement on 7-point clinical symptoms scale was 8 days vs. 10 days with eclitasertib vs. placebo (p = 0.38). Mean ventilator/respiratory failure-free days, change in baseline-adjusted SpO2/FiO2 ratio, and clinical biomarkers showed consistent numerical improvements with eclitasertib vs. placebo. The most frequently reported treatment-emergent adverse events were gastrointestinal disorders and condition aggravated/worsened COVID-19 pneumonia. Eclitasertib was well tolerated with consistent trends toward more rapid resolution of inflammatory biomarkers and clinical improvement in severe COVID-19 patients than placebo.[1]

SAR443122 (eclitasertib) is a highly potent, selective oral inhibitor of RIPK1 kinase activity under development as an immunomodulatory drug for cutaneous lupus erythematosus and ulcerative colitis. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is an intracellular protein that regulates the downstream signalling of tumour necrosis factor receptor 1 (TNFR1), toll-like receptors (TLRs) 3 and 4, and interferon receptors (IFNRs), by exhibiting both kinase activity-dependent and kinase activity-independent functions. RIPK1-mediated signalling promotes inflammation and induces apoptotic or necroptotic cell death. Both RIPK1 kinase-driven inflammation and cell death are key contributors to tumour necrosis factor-alpha (TNF-α)-induced systemic inflammatory response syndrome (SIRS). Moreover, RIPK1 kinase inhibition may suppress vascular dysfunction, endothelial/epithelial cell damage and exacerbated inflammatory signalling. It could complement antiviral therapy by inhibiting the inflammatory surge and necroptosis of pulmonary epithelial cells, preventing, or reducing the effect of severe inflammation on respiratory function and other organ failure. Since RIPK1 is considered a master regulator of proinflammatory cell death, selectively targeting its kinase activity was hypothesised to mitigate the devastating sequelae of the hyperinflammatory state observed in late-stage severe COVID-19.

In this Phase 1b, double-blinded, placebo-controlled study (NCT04469621) a total of 82 patients were screened, of whom 68 patients were eligible and randomized (2:1) to receive eclitasertib 600 mg (300 mg twice daily) or placebo up to 14 days. Primary outcome was relative change in C-reactive protein from baseline to Day 7. Time to clinical improvement using 7-point ordinal scale, ventilator/respiratory failure-free days, change in SpO2/FiO2 ratio, and biomarkers of severe COVID-19 were explored.

[1]. Immunomodulatory and clinical effects of receptor-interacting protein kinase 1 (RIPK1) inhibitor eclitasertib (SAR443122) in patients with severe COVID-19: a phase 1b, randomized, double-blinded, placebo-controlled study. Respir Res. 2024 Feb 28;25(1):107. [2]. Compounds, compositions and methods. WO2017136727A2.

Eclitasertib is a small molecule receptor-interacting serine/threonine protein kinase 1 (RIPK1; receptor-interacting protein 1; RIP1) inhibitor with high oral bioavailability and potential anti-inflammatory and immunomodulatory activities. Oral Eclitasertib blocks RIPK1-mediated signaling, thereby reducing inflammation and the resulting tissue damage. RIPK1 is a signaling protein in the tumor necrosis factor (TNF) receptor pathway, playing a key role in tissue damage and inflammation and cell death induced by pathogen recognition. SAR443122 inhibits receptor-interacting serine/threonine protein kinase 1 (RIPK1). Currently, this drug is being investigated for the treatment of inflammatory diseases such as rheumatoid arthritis and psoriasis, as well as the hyperinflammatory state in patients with severe COVID-19. Background: Targeting receptor-interacting serine/threonine protein kinase 1 (RIN1) may alleviate the severe sequelae of the hyperinflammatory state observed in patients with severe COVID-19. This study aimed to explore the immunomodulatory and clinical efficacy of the RIN1 inhibitor SAR443122 (eclitasertib) in patients with severe COVID-19. Methods: In this phase 1b, double-blind, placebo-controlled study (NCT04469621), 82 patients were screened, of whom 68 met the inclusion criteria and were randomly assigned in a 2:1 ratio to receive either eclitasertib 600 mg (300 mg twice daily) or placebo for a maximum duration of 14 days. The primary endpoint was the relative change in C-reactive protein from baseline to day 7. The study also investigated time to clinical improvement, days without mechanical ventilation/days without respiratory failure, changes in the SpO2/FiO2 ratio, and biomarkers of severe COVID-19, as assessed using a 7-point ordinal scoring system. Results: On day 7, the geometric mean odds ratio (point estimate [90% confidence interval]) of the relative change in C-reactive protein from baseline was 0.85 in the eclitasertib group compared to the placebo group (0.49–1.45; p = 0.30). The median time to a 50% decrease in C-reactive protein from baseline was 3 days in the eclitasertib group compared to the placebo group (p = 0.056). The median time to an improvement of ≥2 points in the 7-point clinical symptom score was 8 days in the eclitasertib group compared to the placebo group (p = 0.38). Compared to placebo, patients in the eclitasertib group showed consistent numerical improvements in mean ventilator-free/respiratory failure-free days, baseline-adjusted SpO2/FiO2 ratio, and clinical biomarkers. The most common adverse events during treatment were gastrointestinal problems and exacerbations of COVID-19 pneumonia. Conclusion: Eclitasertib was well tolerated and, compared with placebo, showed a sustained trend toward resolution of inflammatory biomarkers and clinical improvement in patients with severe COVID-19. [1]

C19H18N6O3

378.38462305069

378.144

C, 60.31; H, 4.80; N, 22.21; O, 12.68

2125450-76-0

130298939

White to light yellow solid

1.7

2

6

4

28

570

1

O1C2=CC=CN=C2N(C)C([C@H](C1)NC(C1=NNC(CC2C=CC=CC=2)=N1)=O)=O

XUZICJHIIJCKQQ-ZDUSSCGKSA-N

InChI=1S/C19H18N6O3/c1-25-17-14(8-5-9-20-17)28-11-13(19(25)27)21-18(26)16-22-15(23-24-16)10-12-6-3-2-4-7-12/h2-9,13H,10-11H2,1H3,(H,21,26)(H,22,23,24)/t13-/m0/s1

(S)-3-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-5-carboxamide

DNL-758; Eclitasertib; 2125450-76-0; Eclitasertib [INN]; Eclitasertib [USAN]; SAR443122;DNL 758; SAR-443122; DNL758; SAR 443122;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~125 mg/mL (~330.36 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (5.50 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 20.8 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.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (5.50 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 20.8 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.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (5.50 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)