Synonym
LDC1267; LDC-1267; LDC 1267.
IUPAC/Chemical Name
N-[4-[(6,7-dimethoxy-4-quinolyl)oxy]-3-fluoro-phenyl]-4-ethoxy-1-(4-fluoro-2-methyl-phenyl)pyrazole-3-carboxamide
InChi Key
ISPBCAXOSOLFME-UHFFFAOYSA-N
InChi Code
InChI=1S/C30H26F2N4O5/c1-5-40-28-16-36(23-8-6-18(31)12-17(23)2)35-29(28)30(37)34-19-7-9-25(21(32)13-19)41-24-10-11-33-22-15-27(39-4)26(38-3)14-20(22)24/h6-16H,5H2,1-4H3,(H,34,37)
SMILES Code
O=C(C1=NN(C2=CC=C(F)C=C2C)C=C1OCC)NC3=CC=C(OC4=CC=NC5=CC(OC)=C(OC)C=C45)C(F)=C3
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, not in water
Shelf Life
>2 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
Biological target:
LDC1267 is a highly selective TAM (Tyro3, Axl and Mer) kinase inhibitor with IC50s of <5 nM/8 nM/29 nM for Tyro3,Axl and Mer respectively.
In vitro activity:
To assess whether modulation of the TAM/Cbl-b inhibitory pathway could be used for anti-tumor immunotherapy, a highly selective TAM kinase inhibitor, termed LDC1267. LDC1267 was developed and preferentially inhibits Tyro3, Axl, and Mer at low nanomolarity, as determined by tracer-based binding assays (Fig. 3d,e). Selectivity of LDC1267 was further assessed using a cell-free KINOMEscan assay covering 456 kinases (Fig. 3f, Supplementary Table 1). Cellular selectivity was confirmed employing a quantitative chemical proteomics approach, cell-based phosphorylation, and proliferation assays (Extended Data Fig. 9a-d). Treatment of NKG2D-activated NK cells with LDC1267 indeed abolished the inhibitory effects of Gas6 stimulation; LDC1267 had no apparent additional effect in Cbl-b deficient NK cells (Fig. 3g).
Reference: Nature. 2014 Mar 27; 507(7493): 508–512. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258903/
In vivo activity:
In vivo, wild-type mice treated with LDC1267 showed enhanced cytotoxicity towards RMA cells overexpressing the NKGD2 ligand Rae-1 (RMA-Rae1) to the same extent as C373AKI/KI mice, but had no effect on the already enhanced NK cytotoxicity in Cbl-bdeficient mice (Fig. 3h; Extended Data 9e). To provide definitive proof that LDC1267 treatment can license NK cells to kill, B16F10 melanoma-bearing mice were treated with NK cells that were either untreated or treated ex vivo with our TAM inhibitor (Extended Data Fig. 9f). Adoptive transfer of LDC1267-treated wild-type NK cells significantly increased the anti-tumor response to levels observed in mice transplanted with Cbl-b-/- NK cells, but did not increase the anti-metastatic efficacy of Cbl-b knock-out NK cells (Fig. 3i), reinforcing the notion that Cbl-b acts downstream of TAM receptors for NK cell inhibition. These results indicate that TAM receptor inhibition using LDC1267 unleashes NK cells to kill tumors cells in vivo.
Reference: Nature. 2014 Mar 27; 507(7493): 508–512. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258903/
|
Solvent |
mg/mL |
mM |
comments |
| Solubility |
| DMSO |
50.0 |
89.20 |
|
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
560.56
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. Paolino M, Choidas A, Wallner S, Pranjic B, Uribesalgo I, Loeser S, Jamieson AM, Langdon WY, Ikeda F, Fededa JP, Cronin SJ, Nitsch R, Schultz-Fademrecht C, Eickhoff J, Menninger S, Unger A, Torka R, Gruber T, Hinterleitner R, Baier G, Wolf D, Ullrich A, Klebl BM, Penninger JM. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature. 2014 Mar 27;507(7493):508-12. doi: 10.1038/nature12998. Epub 2014 Feb 19. PMID: 24553136; PMCID: PMC6258903.
2. Zou Z, Sun J, Kang Z, Wang Y, Zhao H, Zhu K, Wang J. Tyrosine Kinase Receptors Axl and MerTK Mediate the Beneficial Effect of Electroacupuncture in a Cuprizone-Induced Demyelinating Model. Evid Based Complement Alternat Med. 2020 Jul 4;2020:3205176. doi: 10.1155/2020/3205176. PMID: 32714402; PMCID: PMC7355344. 2
In vitro protocol:
1. Paolino M, Choidas A, Wallner S, Pranjic B, Uribesalgo I, Loeser S, Jamieson AM, Langdon WY, Ikeda F, Fededa JP, Cronin SJ, Nitsch R, Schultz-Fademrecht C, Eickhoff J, Menninger S, Unger A, Torka R, Gruber T, Hinterleitner R, Baier G, Wolf D, Ullrich A, Klebl BM, Penninger JM. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature. 2014 Mar 27;507(7493):508-12. doi: 10.1038/nature12998. Epub 2014 Feb 19. PMID: 24553136; PMCID: PMC6258903.
In vivo protocol:
1. Zou Z, Sun J, Kang Z, Wang Y, Zhao H, Zhu K, Wang J. Tyrosine Kinase Receptors Axl and MerTK Mediate the Beneficial Effect of Electroacupuncture in a Cuprizone-Induced Demyelinating Model. Evid Based Complement Alternat Med. 2020 Jul 4;2020:3205176. doi: 10.1155/2020/3205176. PMID: 32714402; PMCID: PMC7355344. 2. Paolino M, Choidas A, Wallner S, Pranjic B, Uribesalgo I, Loeser S, Jamieson AM, Langdon WY, Ikeda F, Fededa JP, Cronin SJ, Nitsch R, Schultz-Fademrecht C, Eickhoff J, Menninger S, Unger A, Torka R, Gruber T, Hinterleitner R, Baier G, Wolf D, Ullrich A, Klebl BM, Penninger JM. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature. 2014 Mar 27;507(7493):508-12. doi: 10.1038/nature12998. Epub 2014 Feb 19. PMID: 24553136; PMCID: PMC6258903.
1: Paolino M, Choidas A, Wallner S, Pranjic B, Uribesalgo I, Loeser S, Jamieson
AM, Langdon WY, Ikeda F, Fededa JP, Cronin SJ, Nitsch R, Schultz-Fademrecht C,
Eickhoff J, Menninger S, Unger A, Torka R, Gruber T, Hinterleitner R, Baier G,
Wolf D, Ullrich A, Klebl BM, Penninger JM. The E3 ligase Cbl-b and TAM receptors
regulate cancer metastasis via natural killer cells. Nature. 2014 Mar
27;507(7493):508-12. doi: 10.1038/nature12998. Epub 2014 Feb 19. PubMed PMID:
24553136.
