Ladarixin (DF2156A), an investigational small-molecule drug, is a potent, orally bioavailable, non-competitive, dual allosteric inhibitor of CXCR1 and CXCR2 interleukin-8 (IL-8A and IL-8B, respectively). In preclinical studies, ladarixin was shown to prevent and reverse diabetes in NOD mice. The potency of CXCR1/2 inhibition may prevent inflammation- and autoimmunity-mediated damage of pancreatic islets. CXCR1/2 inhibition blocks and reverses type 1 diabetes in mice.

Physicochemical Properties

Molecular Formula	C11H12F3NO6S2
Molecular Weight	375.3332
Exact Mass	375.006
CAS #	849776-05-2
Related CAS #	Ladarixin sodium;865625-56-5
PubChem CID	11372270
Appearance	White to off-white solid powder
LogP	4.096
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	9
Rotatable Bond Count	5
Heavy Atom Count	23
Complexity	624
Defined Atom Stereocenter Count	1
SMILES	C[C@H](C1=CC=C(C=C1)OS(=O)(=O)C(F)(F)F)C(=O)NS(=O)(=O)C
InChi Key	DDLPYOCJHQSVSZ-SSDOTTSWSA-N
InChi Code	InChI=1S/C11H12F3NO6S2/c1-7(10(16)15-22(2,17)18)8-3-5-9(6-4-8)21-23(19,20)11(12,13)14/h3-7H,1-2H3,(H,15,16)/t7-/m1/s1
Chemical Name	4-((2R)-1-Oxo-1-(methanesulfonamido)propan-2-yl)phenyl trifluoromethanesulfonate
Synonyms	DF-2156A DF2156A DF 2156A DF-2156 DF2156 DF 2156 Ladarixin
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ln Vitro	Human polymorphonuclear leukocytes (PMN) are inhibited in their migration to CXCL8 by ladararixin (IC50, 0.7 nM) [2].
ln Vivo	In a single OVA exposure scenario, ladararixin (10 mg/kg; oral once daily) decreases allergic airway variables. Ladararixin (10 mg/kg; face once daily for 8 days) decreases pulmonary bleomycin in mice effects in vivo and fibrosis[1]. Ladararixin attenuates allergic airway factors, cough, and asthmatic hyperresponsiveness in a chronic OVA exposure paradigm. Ladararixin (10 mg/kg); once daily for three days on the face. days) to shield the nails from recurrent harmful infections brought on by cigarette smoking [1]. In several animal models, ladarixin cardiotype dramatically lowers systemic neutrophils without appreciably affecting CXCL8-induced polymorphonuclear leukocyte respiration.
Animal Protocol	Animal/Disease Models: Mouse (cigarette smoke-induced exacerbation of influenza A virus infection model) [ 1] Doses: 10 mg/kg Route of Administration: Po one time/day on days 2, 3 and 4 after infection. Experimental Results: Cell count [2]. The worsening of lethality and respiratory changes noted in the CSFlu group was Dramatically attenuated.
References	[1]. CXCR1 and CXCR2 Inhibition by Ladarixin Improves Neutrophil-Dependent Airway Inflammation in Mice. Front Immunol. 2020 Oct 2;11:566953. [2]. Ladarixin, a dual CXCR1/2 inhibitor, attenuates experimental melanomas harboring different molecular defects by affecting malignant cells and tumor microenvironment. Oncotarget. 2017 Feb 28;8(9):14428-14442.
Additional Infomation	Ladarixin is under investigation in clinical trial NCT04628481 (A Study of Oral Ladarixin in New-onset Type 1 Diabetes and a Low Residual Β-Cell Function). Ladarixin is an orally bioavailable, small molecule, dual inhibitor of C-X-C motif chemokine receptors 1 (CXCR1) and 2 (CXCR2), with potential anti-inflammatory and antineoplastic activities. Upon oral administration, ladarixin selectively targets and allosterically binds to CXCR 1 and 2, thereby preventing CXCR1 and CXCR2 activation by their ligand and pro-inflammatory chemokine interleukin 8 (IL-8 or CXCL8). This inhibits CXCR1/2-mediated signaling, which inhibits inflammatory processes, reduces both the recruitment and migration of immunosuppressive myeloid-derived suppressor cells (MDSCs) and neutrophils in the tumor microenvironment (TME), and abrogates the immunosuppressive-induced nature of the TME. This allows effector cells, such as natural killer (NK) cells and cytotoxic T-lymphocytes (CTLs), to kill and eliminate cancer cells, and inhibits tumor cell migration, metastasis, angiogenesis and tumor cell proliferation. CXCR1 and 2, G protein-coupled receptor proteins located on myeloid cells and certain tumor cells, play key roles in the immunosuppressive nature of the TME, tumor metastasis, resistance to chemotherapeutic agents and myeloid cell suppression. They also play a key role in inflammation and their expression is elevated in several inflammatory-driven diseases. Drug Indication Treatment of type I diabetes mellitus

Solubility Data

Solubility (In Vitro)

DMSO : ~100 mg/mL (~266.43 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.66 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 25.0 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.66 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 25.0 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. Solubility in Formulation 3: ≥ 2.5 mg/mL (6.66 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 10 mg/mL (26.64 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.6643 mL	13.3216 mL	26.6432 mL
	5 mM	0.5329 mL	2.6643 mL	5.3286 mL
	10 mM	0.2664 mL	1.3322 mL	2.6643 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.