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| Targets |
DGY-06-116 targets Src, a non-receptor tyrosine kinase that plays a critical role in cell proliferation, migration, survival, and angiogenesis. Src is frequently overactivated in various cancers and is a validated target for cancer therapy. As an irreversible covalent inhibitor, DGY-06-116 forms a covalent bond with Src, similar to SM1-71, where the P-loop must kink to establish the covalent bond. The compound also inhibits FGFR1 with an IC50 of 8340 nM.
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| ln Vitro |
DGY-06-116 has an IC50 of 2.6 nM at 1 hour, which is an efficient inhibitor of Src activation [2]. In cell lines with SRC activation from non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC), DGY-06-116 (Compound 15a; 0.01-10 μM; 72) demonstrates strong anti-apoptotic effects [1]. In NSCLC cells, 15a (1 μM; 2 hours) significantly inhibits SRC binding and SRC signaling [1].
In vitro, DGY-06-116 inhibits Src with an IC50 of 2.6 nM. It also inhibits FGFR1 with an IC50 of 8340 nM. DGY-06-116 exhibits potent antiproliferative effects in Src-activated cell lines of non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC). The compound's irreversible covalent binding to Src provides sustained target inhibition, making it valuable for studying Src-driven cancer biology. |
| ln Vivo |
DGY-06-116 (Compound 15a; 5 mg/kg, paired with 3 i.p. injections every 12 hours) is able to suppress SRC over lengthy periods of time in C57B6 mice, presumably because to its capacity to covalently target [1]. 06-116 ip medication (5 mg) has a short half-life and high exposure (T1/2=1.29 h, AUC=12 746.25 min·ng/mL)/kg) B6 mice [1].
In vivo, DGY-06-116 has potential for studying Src-driven cancers including NSCLC and TNBC. By irreversibly inhibiting Src, the compound may reduce tumor growth and metastasis. However, specific in vivo efficacy data and dosing details have not been extensively detailed in the available literature. Further preclinical studies would be required. |
| Enzyme Assay |
For in vitro kinase assays, recombinant Src or FGFR1 proteins are incubated with a peptide substrate and ATP in kinase assay buffer. The test compound is added at various concentrations (0.001-1000 nM). Kinase activity is measured using radioactive ATP incorporation or luminescent ADP detection assays. IC50 values are calculated by fitting dose-response curves.
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| Cell Assay |
Cell proliferation assay [1]
Cell Types: H1975 (non-small cell lung cancer, NSCLC), HCC827 (NSCLC) and MDA-MB-231 (triple-negative breast cancer, TNBC) cell line Tested Concentrations: 0.01, 0.1, 1, ]. 10 μM Incubation Duration: 72 hrs (hours) Experimental Results: Strong growth inhibition of all three cell lines with GR50 values of 0.3, 0.5 and 0.3 μM for H1975, HCC827 and MDA-MB-231 respectively. Western Blot Analysis[1] Cell Types: H1975 and HCC827 NSCLC Cell Tested Concentrations: 1 μM Incubation Duration: 2 hrs (hours) Experimental Results: p-SRCY416 signaling was inhibited in H1975 and HCC827 cells. For cell proliferation assays, cancer cell lines (such as NSCLC or TNBC cell lines) are seeded in 96-well plates and treated with DGY-06-116 at concentrations ranging from 0.01-10 µM for 72 hours. Cell viability is assessed using MTT or CellTiter-Glo assays. IC50 values are calculated from dose-response curves. Src phosphorylation and downstream signaling are assessed by Western blotting to confirm target inhibition. |
| Animal Protocol |
Animal/Disease Models: Adult C57B6 mice[1]
Doses: 5 mg/kg Route of Administration: intraperitoneal (ip) injection; 3 times every 12 hrs (hrs (hours)) Experimental Results: Compared with vehicle control, induced p-SRCY416 at 2 hrs (hrs (hours)) and 4 hrs (hrs (hours)) after administration inhibition. SRC binding and inhibition were demonstrated at both 2 and 4 hrs (hrs (hours)) post-dose compared to vehicle control. For in vivo efficacy studies, immunodeficient mice would be implanted with NSCLC or TNBC xenografts. When tumors reach a predetermined size, mice would be randomized and treated with DGY-06-116 via appropriate routes at doses determined from pharmacokinetic studies. Tumor volumes would be measured twice weekly. At study endpoint, tumors would be collected for analysis of Src inhibition and downstream signaling. |
| ADME/Pharmacokinetics |
DGY-06-116 is soluble in DMSO at 100 mg/mL (167.47 mM). It is insoluble in water and ethanol. For in vivo administration, it can be formulated as a homogeneous suspension in CMC-Na at ≥5 mg/mL. Storage is recommended at -20°C for powder (3 years) and -20°C for solutions.
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| Toxicity/Toxicokinetics |
DGY-06-116 is a research compound intended for laboratory use only and is not for human or veterinary use. As an irreversible covalent inhibitor, it may have off-target effects and should be handled with appropriate safety precautions. Comprehensive toxicology studies would be required before any clinical development.
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| References | |
| Additional Infomation |
DGY-06-116 is an irreversible covalent and selective Src inhibitor with an IC50 of 2.6 nM. It also inhibits FGFR1 with an IC50 of 8340 nM. DGY-06-116 exhibits potent antiproliferative effects in Src-activated NSCLC and TNBC cell lines. It is a research tool and is not approved for clinical use.
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| Molecular Formula |
C32H33CLN8O2
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|---|---|
| Molecular Weight |
597.109824895859
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| Exact Mass |
596.241
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| CAS # |
2556836-50-9
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| PubChem CID |
154573782
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| Appearance |
White to off-white solid powder
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| LogP |
6
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
43
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| Complexity |
925
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1=CC=CC(C)=C1NC(C1C=NC(=NC=1NC1C=CC=CC=1NC(C=C)=O)NC1C=CC(=CC=1)N1CCN(C)CC1)=O
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| InChi Key |
HLRQYOGLZWIOPA-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C32H33ClN8O2/c1-4-28(42)36-26-10-5-6-11-27(26)37-30-24(31(43)38-29-21(2)8-7-9-25(29)33)20-34-32(39-30)35-22-12-14-23(15-13-22)41-18-16-40(3)17-19-41/h4-15,20H,1,16-19H2,2-3H3,(H,36,42)(H,38,43)(H2,34,35,37,39)
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| Chemical Name |
N-(2-chloro-6-methylphenyl)-2-[4-(4-methylpiperazin-1-yl)anilino]-4-[2-(prop-2-enoylamino)anilino]pyrimidine-5-carboxamide
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO : ~250 mg/mL (~418.68 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.48 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 20.8 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: ≥ 2.08 mg/mL (3.48 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6747 mL | 8.3737 mL | 16.7473 mL | |
| 5 mM | 0.3349 mL | 1.6747 mL | 3.3495 mL | |
| 10 mM | 0.1675 mL | 0.8374 mL | 1.6747 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.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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