ADH-503 Choline | CAS#2055362-74-6 | CD11b Agonist

MedKoo Cat#: 408039 | Name: ADH-503

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Description:

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

ADH-503 is a potent agonist of the integrin CD11b to mitigate myeloid cell immunosuppression. The partial activation of CD11b by ADH-503 leads to the repolarization of tumor-associated macrophages, reduction in the number of tumor-infiltrating immunosuppressive myeloid cells, and enhanced dendritic cell responses. These actions, in turn, improve antitumor T cell immunity and render checkpoint inhibitors effective in previously unresponsive PDAC models.

Chemical Structure

ADH-503

CAS#2055362-74-6 (choline)

Theoretical Analysis

MedKoo Cat#: 408039

Name: ADH-503

CAS#: 2055362-74-6 (choline)

Chemical Formula: C27H28N2O5S2

Exact Mass: 0.0000

Molecular Weight: 524.65

Elemental Analysis: C, 61.81; H, 5.38; N, 5.34; O, 15.25; S, 12.22

Price and Availability

Size	Price	Availability	Quantity
1g	USD 3,450.00	2 months
2g	USD 5,650.00	2 months

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Related CAS #

2055362-72-4 (free base) 2055362-74-6 (choline)

Synonym

ADH-503; ADH 503; ADH503; Leukadherin-1 choline salt; LA1; ADH-503 choline,

IUPAC/Chemical Name

2-hydroxy-N,N,N-trimethylethan-1-aminium (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoate

InChi Key

GOWDQYRMBCOOJR-JHMJKTBASA-M

InChi Code

InChI=1S/C22H15NO4S2.C5H14NO/c24-20-19(29-22(28)23(20)13-14-4-2-1-3-5-14)12-17-10-11-18(27-17)15-6-8-16(9-7-15)21(25)26;1-6(2,3)4-5-7/h1-12H,13H2,(H,25,26);7H,4-5H2,1-3H3/q;+1/p-1/b19-12-;

SMILES Code

C[N+](C)(C)CCO.O=C([O-])C1=CC=C(C2=CC=C(/C=C(SC(N3CC4=CC=CC=C4)=S)/C3=O)O2)C=C1

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

Although checkpoint immunotherapies have revolutionized the treatment of cancer, not all tumor types have seen substantial benefit. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy in which very limited responses to immunotherapy have been observed. Extensive immunosuppressive myeloid cell infiltration in PDAC tissues has been postulated as a major mechanism of resistance to immunotherapy. Strategies concomitantly targeting monocyte or granulocyte trafficking or macrophage survival, in combination with checkpoint immunotherapies, have shown promise in preclinical studies, and these studies have transitioned into ongoing clinical trials for the treatment of pancreatic and other cancer types.

Product Data

Product Data

Instruction

View handling instruction

Biological target:

ADH-503 ((Z)-Leukadherin-1 choline) is an orally active and allosteric CD11b agonist.

In vitro activity:

To examine the direct effects of ADH-503 on the responses of macrophages to tumor-derived factors, this study treated bone marrow-derived macrophages with conditioned medium from KPC-derived PDAC cells in the presence or absence of ADH-503, and then examined the gene expression levels of key cytokines by Q-PCR and RNA sequencing (RNA-seq). RNA-seq analysis showed that greater than 8000 RNAs were changes by 2 fold within 6 hours of ADH-503 exposure (Fig. 2F). Ontological analyses of these gene sets showed key changes in genes involved in antigen presentation and processing, lysosomal trafficking, phagocytosis and interleukin (IL)-8 signaling (Fig. 2G). Further analyses of these data also show that ADH-503 rapidly decreased the genes involved in IL-1 signaling, increased the expression of cytokines involved in T cell and DC trafficking, and reduced the regulatory T cell recruitment of cytokines CCL17 and 22 (Fig. 2H). Results from a parallel Q-PCR analysis in a second experiment revealed that ADH-503 down-regulated TGFβ1, IL1α, and IL1β, and reduced the levels of alternative activation markers Arg1, YM1, and Retnlα, while upregulating type I interferons (IFNα1 and β) and T cell recruitment factors (CXCL9, 10, and 11, Fig. 2I). Taken together, these data suggest that ADH-503 results in the repolarization of macrophages towards a phenotype that could support anti-tumor T cell responses. Reference: Sci Transl Med. 2019 Jul 3; 11(499): eaau9240. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197026/

In vivo activity:

To determine whether CD11b agonism can improve anti-tumor immunity, this study explored changes in tumor T cell infiltration and phenotype in two orthotopic PDAC models and in KPC mice. This study analyzed tumor-infiltrating T cells and found that ADH-503 treatment resulted in increased numbers of total CD8+ cytotoxic T lymphocytes (CTLs) and CD4+ T effectors (Figs. 4A–D and S4A). In addition to increasing T cell frequency, ADH-503 also increased CD8+ CTL and CD4+ effector cell proliferation (Ki67+ CD8+ CTLs) and activation (CD44Hi CD62Lneg) (Fig. 4A–D). In contrast, this study found reduced numbers of FOXP3+ regulatory T cells (Treg) and a better CD8+ CTL to Treg ratio in PDAC tissues from ADH-503-treated mice (Figs. 4B and S4A–B). This study found that although the distribution of CD8+ T cells was not markedly changed over distances of 30–150 μm, the number and frequency of CD8+ T cells in close proximity to PDAC cells were changed by ADH-503 treatment (Fig. 4E). In vehicle-treated mice, CD8+ T cells were in very limited numbers at distances of less than 25 μm, with nearly no CTLs at distances <10 μm. In contrast, ADH-503 treatment significantly increased the number of CD8+ CTLs in direct contact (< 5 μm) and in close proximity (< 25 μm) to CK19+ PDAC cells. Reference: Sci Transl Med. 2019 Jul 3; 11(499): eaau9240. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197026/

	Solvent	mg/mL	mM	comments
Solubility
	DMSO	21.4	40.85

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 524.65 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. Panni RZ, Herndon JM, Zuo C, Hegde S, Hogg GD, Knolhoff BL, Breden MA, Li X, Krisnawan VE, Khan SQ, Schwarz JK, Rogers BE, Fields RC, Hawkins WG, Gupta V, DeNardo DG. Agonism of CD11b reprograms innate immunity to sensitize pancreatic cancer to immunotherapies. Sci Transl Med. 2019 Jul 3;11(499):eaau9240. doi: 10.1126/scitranslmed.aau9240. PMID: 31270275; PMCID: PMC7197026.

In vitro protocol:

In vivo protocol:

1. RZ Panni et al. Agonism of CD11b reprograms innate immunity to sensitize pancreatic cancer to immunotherapies. Sci Transl Med. 2019 Jul 3;11(499). 2. I Dickson. CD11b agonism overcomes PDAC immunotherapy resistance. Nat Rev Gastroenterol Hepatol. 2019 Sep;16(9):514. 3. D Maiguel et al. Small molecule-mediated activation of the integrin CD11b/CD18 reduces inflammatory disease. Sci Signal. 2011 Sep 6;4(189):ra57.