Synonym
CDKI-73; CDKI 73; CDKI73; LS-007; LS 007; LS007; asnuciclib; asnuciclib [INN];
IUPAC/Chemical Name
3-(5-fluoro-4-(4-methyl-2-(methylamino)thiazol-5-yl)pyrimidin-2-ylamino)benzene sulfonamide
InChi Key
GAIOPWBQKZMUNO-UHFFFAOYSA-N
InChi Code
InChI=1S/C15H15FN6O2S2/c1-8-13(25-15(18-2)20-8)12-11(16)7-19-14(22-12)21-9-4-3-5-10(6-9)26(17,23)24/h3-7H,1-2H3,(H,18,20)(H2,17,23,24)(H,19,21,22)
SMILES Code
O=S(C1=CC=CC(NC2=NC=C(F)C(C3=C(C)N=C(NC)S3)=N2)=C1)(N)=O
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
>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:
CDKI-73 (LS-007) is a potent CDK inhibitor in vitro with IC50 of 8.17 nM, 3.27 nM, 8.18 nM, and 5.78 nM for CDK1, CDK2, CDK4, and CDK9, respectively.
In vitro activity:
The cellular mechanism of a novel CDK9 inhibitor CDKI-73 in an ovarian cancer cell line (A2780) is herein reported. A shRNA-mediated CDK9 knockdown was used to investigate the importance of CDK9 in the maintenance of A2780 cells. This study revealed that CDKI-73 rapidly inhibited cellular CDK9 kinase activity and down-regulated the RNAPII phosphorylation. This subsequently caused a decrease in the eIF4E phosphorylation by blocking Mnk1 kinase activity. Consistently, CDK9 shRNA was also found to down-regulate the Mnk1 expression. Both CDKI-73 and CDK9 shRNA decreased anti-apoptotic proteins Mcl-1 and Bcl-2 and induced apoptosis. The study confirmed that CDK9 is required for cell survival and that ovarian cancer may be susceptible to CDK9 inhibition strategy. The data also implied a role of CDK9 in eIF4E-mediated translational control, suggesting that CDK9 may have important implication in the Mnk-eIF4E axis, the key determinants of PI3K/Akt/mTOR- and Ras/Raf/MAPK-mediated tumorigenic activity. As such, CDK9 inhibitor drug candidate CDKI-73 should have a major impact on these pathways in human cancers.
Reference: Oncotarget. 2014 Sep 15;5(17):7691-704. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25277198/
In vivo activity:
To determine the in vivo anti-leukemic efficacy of CDKI-73, two xenograft studies were performed. In the first study, two groups of MV4–11 tumor bearing mice (n = 8 per group) were administered vehicle i.e. 1% sodium carboxymethylcellulose (CMC) in water or 25 mg/kg CDKI-73 orally once every day for 33 days. Mice were observed daily during dosing and for a further 50 days afterwards. CDKI-73 caused a remarkable delay in tumor growth (Fig. 5b and c) compared to vehicle-treated mice, as reflected in a percentage for the mean tumor volume in treated to control mice (T/C, Eq. 1,Supplementary methods) of 43% at day 31 (P < 0.00001). There was a statistically significant reduction in tumor growth (P < 0.05) from day 11 onwards compared to the vehicle treated group, and tumors regressed completely in two out of eight mice. These delays in growth and regression of tumor translated to an increase in life-span (ILS) of 54.5% (P < 0.001) for the CDKI-73 treated animals compared to the vehicle treated group (Fig. 5d). CDKI-73 was well tolerated as evident from the absence of loss in body weight and other overt toxicities.
Reference: Invest New Drugs. 2019 Aug;37(4):625-635. https://doi.org/10.1007/s10637-018-0661-2
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO |
52.0 |
131.83 |
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
394.44
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 |
In vitro protocol:
1. Lam F, Abbas AY, Shao H, Teo T, Adams J, Li P, Bradshaw TD, Fischer PM, Walsby E, Pepper C, Chen Y, Ding J, Wang S. Targeting RNA transcription and translation in ovarian cancer cells with pharmacological inhibitor CDKI-73. Oncotarget. 2014 Sep 15;5(17):7691-704. doi: 10.18632/oncotarget.2296. PMID: 25277198; PMCID: PMC4202154.
2. Sorvina A, Shandala T, Wang S, Sharkey DJ, Parkinson-Lawrence E, Selemidis S, Brooks DA. CDKI-73 is a Novel Pharmacological Inhibitor of Rab11 Cargo Delivery and Innate Immune Secretion. Cells. 2020 Feb 5;9(2):372. doi: 10.3390/cells9020372. PMID: 32033486; PMCID: PMC7072129.
In vivo protocol:
1. Rahaman MH, Yu Y, Zhong L, Adams J, Lam F, Li P, Noll B, Milne R, Peng J, Wang S. CDKI-73: an orally bioavailable and highly efficacious CDK9 inhibitor against acute myeloid leukemia. Invest New Drugs. 2019 Aug;37(4):625-635. doi: 10.1007/s10637-018-0661-2. Epub 2018 Sep 8. PMID: 30194564.
1: Cao S, Yu Y, Chen S, Lei D, Wang S, Pan X, Peng J. Inhibition of CDK9 induces apoptosis and potentiates the effect of cisplatin in hypopharyngeal carcinoma cells. Biochem Biophys Res Commun. 2017 Jan 22;482(4):536-541. doi: 10.1016/j.bbrc.2016.11.049. Epub 2016 Nov 12. PubMed PMID: 27847320.
2: Xie S, Jiang H, Zhai XW, Wei F, Wang SD, Ding J, Chen Y. Antitumor action of CDK inhibitor LS-007 as a single agent and in combination with ABT-199 against human acute leukemia cells. Acta Pharmacol Sin. 2016 Nov;37(11):1481-1489. doi: 10.1038/aps.2016.49. Epub 2016 Aug 29. PubMed PMID: 27569395; PubMed Central PMCID: PMC5099409.
3: Lam F, Abbas AY, Shao H, Teo T, Adams J, Li P, Bradshaw TD, Fischer PM, Walsby E, Pepper C, Chen Y, Ding J, Wang S. Targeting RNA transcription and translation in ovarian cancer cells with pharmacological inhibitor CDKI-73. Oncotarget. 2014 Sep 15;5(17):7691-704. PubMed PMID: 25277198; PubMed Central PMCID: PMC4202154.
4: Walsby E, Pratt G, Shao H, Abbas AY, Fischer PM, Bradshaw TD, Brennan P, Fegan C, Wang S, Pepper C. A novel Cdk9 inhibitor preferentially targets tumor cells and synergizes with fludarabine. Oncotarget. 2014 Jan 30;5(2):375-85. PubMed PMID: 24495868; PubMed Central PMCID: PMC3964214.
