Onvoloxastat

Onvoloxastat
Clinical data
Other names	CAD-1005; CAD1005; VLX-1005; VLX1005; ML355; ML-355
Routes of; administration	Oral
Drug class	12-Lipoxygenase inhibitor
Identifiers
	IUPAC name N-(1,3-benzothiazol-2-yl)-4-[(2-hydroxy-3-methoxyphenyl)methylamino]benzenesulfonamide;
CAS Number	1532593-30-8;
PubChem CID	70701426;
IUPHAR/BPS	8752;
DrugBank	DB18307;
UNII	JKU4XCC48Y;
ChEBI	CHEBI:195557;
ChEMBL	ChEMBL3113165;
PDB ligand	ZR5 (PDBe, RCSB PDB);
Chemical and physical data
Formula	C21H19N3O4S2
Molar mass	441.52 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES COC1=CC=CC(=C1O)CNC2=CC=C(C=C2)S(=O)(=O)NC3=NC4=CC=CC=C4S3;
	InChI InChI=1S/C21H19N3O4S2/c1-28-18-7-4-5-14(20(18)25)13-22-15-9-11-16(12-10-15)30(26,27)24-21-23-17-6-2-3-8-19(17)29-21/h2-12,22,25H,13H2,1H3,(H,23,24); Key:OWHBVKBNNRYMIN-UHFFFAOYSA-N;

Onvoloxastat (INNTooltip International Nonproprietary Name; 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 (IC₅₀Tooltip half-maximal inhibitory concentration = 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 2 3 4 5 "VLX 1005". AdisInsight. 20 July 2026. Retrieved 25 July 2026.
1 2 3 4 Tourdot BE, Holinstat M (November 2017). "Targeting 12-Lipoxygenase as a Potential Novel Antiplatelet Therapy". Trends in Pharmacological Sciences. 38 (11): 1006–1015. 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].
1 2 3 Dobrian AD, Morris MA, Taylor-Fishwick DA, Holman TR, Imai Y, Mirmira RG, et al. (March 2019). "Role of the 12-lipoxygenase pathway in diabetes pathogenesis and complications". Pharmacology & Therapeutics. 195: 100–110. doi:10.1016/j.pharmthera.2018.10.010. PMC 6397662. 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.
↑ "INN Proposed List 135". World Health Organization. 19 July 2026.
1 2 3 4 Luci D, Jameson JB, Yasgar A, Diaz G, Joshi N, Kantz A, et al. (2010). "Discovery of ML355, a Potent and Selective Inhibitor of Human 12-Lipoxygenase". Probe Reports from the NIH Molecular Libraries Program. PMID 25506969.
↑ Ma K, Xiao A, Park SH, Glenn L, Jackson L, Barot T, et al. (August 2017). "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. doi:10.1210/jc.2017-00267. PMC 5546865. PMID 28609824.
1 2 D'Silva M, Jackson K, Vaughan MT, Maloney DJ, Gupte SA, Nadler JL, et al. (June 2026). "12-Lipoxygenase (12-LOX) plays a key role in the hyperinflammatory response caused by SARS-CoV-2". mBio. 17 (6) e00738-26: e0073826. doi:10.1128/mbio.00738-26. PMC 13251377. PMID 42059607.
1 2 Adili R, Tourdot BE, Mast K, Yeung J, Freedman JC, Green A, et al. (October 2017). "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. doi:10.1161/ATVBAHA.117.309868. PMC 5620123. PMID 28775075.
↑ Yamaguchi A, Putzbach V, Adili R, Lazar S, Stanger L, Gilmore D, et al. (May 2026). "VLX-1005, but not argatroban, prevents ITAM-mediated platelet activation and heparin-induced thrombocytopenia". Blood Vessels, Thrombosis & Hemostasis. 3 (2) 100146. doi:10.1016/j.bvth.2026.100146. PMC 13019563. PMID 41909515.
↑ Wang X, Tang W, Chen T, Luo L, Liang H (November 2020). "[Antagonistic effect of 12-lipoxygenase inhibitor ML355 on lipopolysaccharide induced inflammatory response in mice]". Zhonghua Wei Zhong Bing Ji Jiu Yi Xue (in Chinese). 32 (11): 1378–1384. doi:10.3760/cma.j.cn121430-20200429-00349. PMID 33463501.

[AdisInsight-1] 1 2 3 4 5 "VLX 1005". AdisInsight. 20 July 2026. Retrieved 25 July 2026.

[TourdotHolinstat2017-2] 1 2 3 4 Tourdot BE, Holinstat M (November 2017). "Targeting 12-Lipoxygenase as a Potential Novel Antiplatelet Therapy". Trends in Pharmacological Sciences. 38 (11): 1006–1015. 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].

[DobrianMorrisTaylor-Fishwick2019-3] 1 2 3 Dobrian AD, Morris MA, Taylor-Fishwick DA, Holman TR, Imai Y, Mirmira RG, et al. (March 2019). "Role of the 12-lipoxygenase pathway in diabetes pathogenesis and complications". Pharmacology & Therapeutics. 195: 100–110. doi:10.1016/j.pharmthera.2018.10.010. PMC 6397662. 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.

[WHO2026-4] "INN Proposed List 135". World Health Organization. 19 July 2026.

[LuciJamesonYasgar2010-5] 1 2 3 4 Luci D, Jameson JB, Yasgar A, Diaz G, Joshi N, Kantz A, et al. (2010). "Discovery of ML355, a Potent and Selective Inhibitor of Human 12-Lipoxygenase". Probe Reports from the NIH Molecular Libraries Program. PMID 25506969.

[MaXiaoPark2017-6] Ma K, Xiao A, Park SH, Glenn L, Jackson L, Barot T, et al. (August 2017). "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. doi:10.1210/jc.2017-00267. PMC 5546865. PMID 28609824.

[D'SilvaJacksonVaughan2026-7] 1 2 D'Silva M, Jackson K, Vaughan MT, Maloney DJ, Gupte SA, Nadler JL, et al. (June 2026). "12-Lipoxygenase (12-LOX) plays a key role in the hyperinflammatory response caused by SARS-CoV-2". mBio. 17 (6) e00738-26: e0073826. doi:10.1128/mbio.00738-26. PMC 13251377. PMID 42059607.

[AdiliTourdotMast2017-8] 1 2 Adili R, Tourdot BE, Mast K, Yeung J, Freedman JC, Green A, et al. (October 2017). "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. doi:10.1161/ATVBAHA.117.309868. PMC 5620123. PMID 28775075.

[YamaguchiPutzbachAdili2026-9] Yamaguchi A, Putzbach V, Adili R, Lazar S, Stanger L, Gilmore D, et al. (May 2026). "VLX-1005, but not argatroban, prevents ITAM-mediated platelet activation and heparin-induced thrombocytopenia". Blood Vessels, Thrombosis & Hemostasis. 3 (2) 100146. doi:10.1016/j.bvth.2026.100146. PMC 13019563. PMID 41909515.

[WangTangChen2020-10] Wang X, Tang W, Chen T, Luo L, Liang H (November 2020). "[Antagonistic effect of 12-lipoxygenase inhibitor ML355 on lipopolysaccharide induced inflammatory response in mice]". Zhonghua Wei Zhong Bing Ji Jiu Yi Xue (in Chinese). 32 (11): 1378–1384. doi:10.3760/cma.j.cn121430-20200429-00349. PMID 33463501.

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