Chemistry:Onvoloxastat

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Onvoloxastat (INN; developmental code names CAD-1005, VLX-1005, and ML355) is a 12-lipoxygenase (12-LOX; ALOX12) inhibitor which is under development for the treatment of heparin-induced thrombocytopenia and thrombosis syndrome (HITTS), acute kidney injury, and diabetes.[1][2][3][4] It is taken orally.[1]

Pharmacology

The drug is a potent, highly selective, non-competitive, and reversible 12-LOX inhibitor (IC50 = 340 nM).[5][6][2][3] It shows anti-inflammatory, antiplatelet, and antithrombotic effects in preclinical research.[5][7][8][2][9] 12-LOX has been found to play a key role in the hyperinflammation induced by severe SARS-CoV-2 infection and onvoloxastat can reduce these responses and improve survival in rodents.[7] The drug also antagonizes lipopolysaccharide (LPS)-induced inflammation.[10]

History

Onvoloxastat was first described in the scientific literature by 2010.[5] It was developed by Cadrenal Therapeutics and Veralox Therapeutics, among other organizations.[1] As of July 2026, the drug is in phase 2 clinical trials for HITTS and is in the preclinical research stage of development for acute kidney injury, type 1 diabetes, and type 2 diabetes.[1] It was among the first selective 12-LOX inhibitors to be discovered and has been described as the "state-of-the-art" inhibitor of this enzyme.[5][8][2][3]

References

  1. ↑ 1.0 1.1 1.2 1.3 "VLX 1005". 20 July 2026. https://adisinsight.springer.com/drugs/800055853. 
  2. ↑ 2.0 2.1 2.2 2.3 "Targeting 12-Lipoxygenase as a Potential Novel Antiplatelet Therapy". Trends in Pharmacological Sciences 38 (11): 1006–1015. November 2017. doi:10.1016/j.tips.2017.08.001. PMID 28863985. "Through an extensive SAR optimization campaign with the 4-((2-hydroxy-3-methoxybenzyl) amino)-benzenesulfonamide-based scaffold researchers have developed ML355 ((N-benzo[d] thiazol-2-yl)-4((2-hydroxy-3 methoxybenzyl)amino)benzenesulfonamide) [5]. ML355 is a nonreductive, noncompetitive, reversible 12-LOX inhibitor with high selectivity (>50-fold) over other oxygenases. Similar to other 12-LOX inhibitors, in vitro ML355 reduces human platelet aggregation in response to low doses of agonists, but the antiplatelet effects of blocking 12-LOX can be overcome at higher concentrations of agonist [5,32].". 
  3. ↑ 3.0 3.1 3.2 "Role of the 12-lipoxygenase pathway in diabetes pathogenesis and complications". Pharmacology & Therapeutics 195: 100–110. March 2019. doi:10.1016/j.pharmthera.2018.10.010. PMID 30347209. "From the same HTS, a benzenesulfonamide was discovered (ML355, Figure 1), whose structure was much more “drug-like.” Its potency was sub-micromolar (IC50 = 0.3 uM), and its selectivity was greater than 100-fold higher compared to both other LOX and COX isozymes (Luci et al., 2014). More importantly, ML355 showed cellular potency in human platelets and mouse bleed models (Tourdot and Holinstat, 2017). ML355 is currently the state-of-the-art for potent/selective 12-LOX inhibitors, and is an appropriate molecule for 12-LOX biological studies.". 
  4. ↑ "INN Proposed List 135". 19 July 2026. https://www.who.int/publications/m/item/inn-pl-135. 
  5. ↑ 5.0 5.1 5.2 5.3 "Discovery of ML355, a Potent and Selective Inhibitor of Human 12-Lipoxygenase". Probe Reports from the NIH Molecular Libraries Program. 2010. PMID 25506969. 
  6. ↑ "12-Lipoxygenase Inhibitor Improves Functions of Cytokine-Treated Human Islets and Type 2 Diabetic Islets". The Journal of Clinical Endocrinology and Metabolism 102 (8): 2789–2797. August 2017. doi:10.1210/jc.2017-00267. PMID 28609824. 
  7. ↑ 7.0 7.1 "12-Lipoxygenase (12-LOX) plays a key role in the hyperinflammatory response caused by SARS-CoV-2". mBio 17 (6): e0073826. June 2026. doi:10.1128/mbio.00738-26. PMID 42059607. 
  8. ↑ 8.0 8.1 "First Selective 12-LOX Inhibitor, ML355, Impairs Thrombus Formation and Vessel Occlusion In Vivo With Minimal Effects on Hemostasis". Arteriosclerosis, Thrombosis, and Vascular Biology 37 (10): 1828–1839. October 2017. doi:10.1161/ATVBAHA.117.309868. PMID 28775075. 
  9. ↑ "VLX-1005, but not argatroban, prevents ITAM-mediated platelet activation and heparin-induced thrombocytopenia". Blood Vessels, Thrombosis & Hemostasis 3 (2). May 2026. doi:10.1016/j.bvth.2026.100146. PMID 41909515. 
  10. ↑ "[Antagonistic effect of 12-lipoxygenase inhibitor ML355 on lipopolysaccharide induced inflammatory response in mice]" (in Chinese). Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 32 (11): 1378–1384. November 2020. doi:10.3760/cma.j.cn121430-20200429-00349. PMID 33463501. 



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