SR-3029 is a potent CK1δ/CK1ε inhibitor, with IC50s of 44 nM and 260 nM, respectively. SR-3029 is ATP competitive, with Kis of 97 nM for CK1δ/CK1ε. SR-3029 also blocks CDK6/cyclin D3, CDK6/cyclin D1, CDK4/cyclin D3, CDK4/cyclin D1 and FLT3, with IC50s of 427, 428, 368, 576, and 3000 nM, respectively. SR-3029 shows inhibitory effects on A375 cells, with an EC50 of 86 nM.
In vitro, SR-3029 shows less potent activities against MCF7 and T47D breast cancer cells and the MCF10A cell line, which express low amounts of CK1δ.
In vivo: SR-3029 (20 mg/kg daily i.p.) exibits anti-tumor effects in rthotopic MDA-MB-231, MDA-MB-468 (TNBC), SKBR3 and BT474 (HER2+) tumor xenografts with no overt toxicity in mice. SR-3029 (20 mg/kg daily i.p.) also effectively inhibits the growth of tumor in primary patient-derived xenograft (PDX) models. In addition, SR-3029 (20 mg/kg, i.p.) strongly reduces the expression of nuclear β-catenin in tumors of mice.
|Cell lines||Human A375 melanoma cells|
|Preparation method||SR-3029 is dissolved in DMSO.
Human A375 melanoma cells are cultured in DMEM supplemented with 10% fetal bovine serum, 1% penicillin/streptomycin and 1× MEM Non-Essential Amino Acids at 37°C, 5% CO2. To evaluate the anti-proliferative activity of newly synthesized CK1δ/ε inhibitors, each compound (SR-3029) is subjected to MTT assays against A375 melanoma cells and their EC50 values are determined. Briefly, A375 melanoma cells are plated into a 96-well plate and treated with a series of concentrations of each new inhibitor, vehicle (DMSO) or with SR-3029 or SR-1277 (positive controls). MTT assays are performed four days after treatment and data are analyzed using the GraphPad Prism5.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO: ≥ 25 mg/mL|
Therapeutic targeting of casein kinase 1δ in breast cancer.
Rosenberg LH, et al. Sci Transl Med. 2015 Dec 16;7(318):318ra202. PMID: 26676609.
Development of highly selective casein kinase 1δ/1ε (CK1δ/ε) inhibitors with potent antiproliferative properties.
Bibian M, et al. Bioorg Med Chem Lett. 2013 Aug 1;23(15):4374-80. PMID: 23787102.
|Related Casein Kinase Products|
LH846 is a selective inhibitor of casein kinase with IC50 values of 290 nM, 1.3 μM and 2.5 μM for CK1δ, ε and α, respectively.
TA-01 potently inhibits CK1ε, CK1δ,and p38α (IC50values are 6.4, 6.8, and 6.7 nM respectively).
TBB(NSC 231634) is a highly selective, ATP/GTP-competitive inhibitor of casein kinase-2 (CK2)with IC50s of 0.9 and 1.6 μM for rat liver and human recombinant CK2 respectively).
TTP 22 is a high affinity, ATP-competitive casein kinase 2 (CK2) inhibitor with IC50/Ki of 0.1 uM/40 nM.
D4476 is a selective inhibitor of casein kinase 1 (CK1) and TGF-β type-I receptor (ALK5) with IC50 of 0.3 µM and 0.5 µM, respectively.
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