WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H200320
CAS#: 902135-91-5 (HCl)
Description: AT-7519 is an orally bioavailable small molecule CDK inhibitor with potential antineoplastic activity. AT7519M selectively binds to and inhibits cyclin dependent kinases (CDKs), which may result in cell cycle arrest, induction of apoptosis, and inhibition of tumor cell proliferation. CDKs are serine/theronine kinases involved in regulation of the cell cycle and may be overexpressed in some types of cancer cells.
Hodoodo Cat#: H200320
Name: AT-7519 HCl
CAS#: 902135-91-5 (HCl)
Chemical Formula: C16H18Cl3N5O2
Exact Mass: 0.00
Molecular Weight: 418.700
Elemental Analysis: C, 45.90; H, 4.33; Cl, 25.40; N, 16.73; O, 7.64
Related CAS #: 902135-91-5 (HCl) 844442-38-2 (free base)
Synonym: AT7519; AT-7519; AT 7519; AT-7519 HCl.
IUPAC/Chemical Name: N-(4-Piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide hydrochloride
InChi Key: PAOFPNGYBWGKCO-UHFFFAOYSA-N
InChi Code: InChI=1S/C16H17Cl2N5O2.ClH/c17-10-2-1-3-11(18)13(10)15(24)22-12-8-20-23-14(12)16(25)21-9-4-6-19-7-5-9;/h1-3,8-9,19H,4-7H2,(H,20,23)(H,21,25)(H,22,24);1H
SMILES Code: O=C(C1=NNC=C1NC(C2=C(Cl)C=CC=C2Cl)=O)NC3CCNCC3.[H]Cl
Appearance: white 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, 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
More Info: Related: 902135-91-5 (AT-7519 HCl salt) 844442-38-2 (AT-7519 free base).
| Biological target: | AT7519 Hydrochloride is an inhibitor of CDKs, with IC50s of 210, 47, 100, 13, 170, and <10 nM for CDK1, CDK2, CDK4 to CDK6, and CDK9, respectively. |
| In vitro activity: | To investigate whether AT7519-induced cytotoxic effects were plausibly due to the apoptosis induction, the binding of annexin-V in combination with PI was analyzed by flow cytometry method. Intriguingly, FACS analysis of annexin-V/PI demonstrated that the inhibition of CDK increased the proportion of both early and late apoptotic cells, which was in agreement with the elevated sub-G1. As presented in Figure 4, AT7519 considerably increased annexin-V-positive NB4 cells from 10.8% in 100 nM to 35.8% in 500 nM of the inhibitor and also enhanced annexin-V/PI double-positive cell from 13.5% to 53.6% in 100 and 500 nM of the inhibitor, respectively. Taken together, these results showed that the inhibition of CDK using AT7519 halted NB4 cell progression, at least partly, through the induction of apoptotic pathway. Reference: Iran J Pharm Res. 2020 Summer; 19(3): 144–155. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758003/ |
| In vivo activity: | Mice were treated daily with i.p. injections of 5, 10 or 15 mg/kg AT7519 in a 5-days on, 2-days off schedule for three weeks consecutively. AT7519 inhibited the growth of AMC711T neuroblastoma xenografts in a dose-dependent manner, with even the lowest dose of 5 mg/kg providing a statistically significant reduction in tumour growth (Fig. 3A and Supplementary Fig. S5A). Treatment with either 10 or 15 mg/kg AT7519 almost completely blocked tumour growth, resulting in a significantly improved anticancer effect compared with 5 mg/kg AT7519 (Fig. 3A). More rapid tumour growth was observed after terminating treatment with AT7519 (Supplementary Fig. S5B). This study also tested AT7519 (15 mg/kg) in MYCN-amplified KCNR neuroblastoma xenografts and found a 50% reduction in tumour growth compared to saline control at day 17 after treatment initiation (Supplementary Fig. S5C). Reference: Clin Cancer Res. 2015 Nov 15; 21(22): 5100–5109. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4645454/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 125.7 | 300.14 | |
| DMF | 30.0 | 71.65 | |
| Ethanol | 16.5 | 39.41 | |
| PBS (pH 7.2) | 0.5 | 1.19 | |
| Water | 43.0 | 102.70 |
The following data is based on the product molecular weight 418.70 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. Pourbagheri-Sigaroodi A, Safaroghli-Azar A, Shanaki M, Yousefi AM, Anjam Najmedini A, Bashash D. Inhibition of Cyclin-dependent Kinase (CDK) Decreased Survival of NB4 Leukemic Cells: Proposing a p53-Independent Sensitivity of Leukemic Cells to Multi-CDKs Inhibitor AT7519. Iran J Pharm Res. 2020 Summer;19(3):144-155. doi: 10.22037/ijpr.2020.113170.14148. PMID: 33680018; PMCID: PMC7758003. 2. Zabihi M, Safaroghli-Azar A, Gharehbaghian A, Allahbakhshian Farsani M, Bashash D. CDK Blockade Using AT7519 Suppresses Acute Myeloid Leukemia Cell Survival through the Inhibition of Autophagy and Intensifies the Anti-leukemic Effect of Arsenic Trioxide. Iran J Pharm Res. 2019 Fall;18(Suppl1):119-131. doi: 10.22037/ijpr.2019.112560.13827. PMID: 32802093; PMCID: PMC7393062. 3. Dolman ME, Poon E, Ebus ME, den Hartog IJ, van Noesel CJ, Jamin Y, Hallsworth A, Robinson SP, Petrie K, Sparidans RW, Kok RJ, Versteeg R, Caron HN, Chesler L, Molenaar JJ. Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma. Clin Cancer Res. 2015 Nov 15;21(22):5100-9. doi: 10.1158/1078-0432.CCR-15-0313. Epub 2015 Jul 22. PMID: 26202950; PMCID: PMC4645454. 4. Alessandri AL, Duffin R, Leitch AE, Lucas CD, Sheldrake TA, Dorward DA, Hirani N, Pinho V, de Sousa LP, Teixeira MM, Lyons JF, Haslett C, Rossi AG. Induction of eosinophil apoptosis by the cyclin-dependent kinase inhibitor AT7519 promotes the resolution of eosinophil-dominant allergic inflammation. PLoS One. 2011;6(9):e25683. doi: 10.1371/journal.pone.0025683. Epub 2011 Sep 30. PMID: 21984938; PMCID: PMC3184151. |
| In vitro protocol: | 1. Pourbagheri-Sigaroodi A, Safaroghli-Azar A, Shanaki M, Yousefi AM, Anjam Najmedini A, Bashash D. Inhibition of Cyclin-dependent Kinase (CDK) Decreased Survival of NB4 Leukemic Cells: Proposing a p53-Independent Sensitivity of Leukemic Cells to Multi-CDKs Inhibitor AT7519. Iran J Pharm Res. 2020 Summer;19(3):144-155. doi: 10.22037/ijpr.2020.113170.14148. PMID: 33680018; PMCID: PMC7758003. 2. Zabihi M, Safaroghli-Azar A, Gharehbaghian A, Allahbakhshian Farsani M, Bashash D. CDK Blockade Using AT7519 Suppresses Acute Myeloid Leukemia Cell Survival through the Inhibition of Autophagy and Intensifies the Anti-leukemic Effect of Arsenic Trioxide. Iran J Pharm Res. 2019 Fall;18(Suppl1):119-131. doi: 10.22037/ijpr.2019.112560.13827. PMID: 32802093; PMCID: PMC7393062. |
| In vivo protocol: | 1. Dolman ME, Poon E, Ebus ME, den Hartog IJ, van Noesel CJ, Jamin Y, Hallsworth A, Robinson SP, Petrie K, Sparidans RW, Kok RJ, Versteeg R, Caron HN, Chesler L, Molenaar JJ. Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma. Clin Cancer Res. 2015 Nov 15;21(22):5100-9. doi: 10.1158/1078-0432.CCR-15-0313. Epub 2015 Jul 22. PMID: 26202950; PMCID: PMC4645454. 2. Alessandri AL, Duffin R, Leitch AE, Lucas CD, Sheldrake TA, Dorward DA, Hirani N, Pinho V, de Sousa LP, Teixeira MM, Lyons JF, Haslett C, Rossi AG. Induction of eosinophil apoptosis by the cyclin-dependent kinase inhibitor AT7519 promotes the resolution of eosinophil-dominant allergic inflammation. PLoS One. 2011;6(9):e25683. doi: 10.1371/journal.pone.0025683. Epub 2011 Sep 30. PMID: 21984938; PMCID: PMC3184151. |
1: Lucas CD, Dorward DA, Tait MA, Fox S, Marwick JA, Allen KC, Robb CT, Hirani N, Haslett C, Duffin R, Rossi AG. Downregulation of Mcl-1 has anti-inflammatory pro-resolution effects and enhances bacterial clearance from the lung. Mucosal Immunol. 2013 Nov 27. doi: 10.1038/mi.2013.102. [Epub ahead of print] PubMed PMID: 24280938.
2: Dolman ME, den Hartog IJ, Molenaar JJ, Schellens JH, Beijnen JH, Sparidans RW. Liquid chromatography-tandem mass spectrometric assay for the cyclin-dependent kinase inhibitor AT7519 in mouse plasma. J Pharm Biomed Anal. 2014 Jan 25;88:216-20. doi: 10.1016/j.jpba.2013.08.051. Epub 2013 Sep 12. PubMed PMID: 24080524.
3: Alessandri AL, Duffin R, Leitch AE, Lucas CD, Sheldrake TA, Dorward DA, Hirani N, Pinho V, de Sousa LP, Teixeira MM, Lyons JF, Haslett C, Rossi AG. Induction of eosinophil apoptosis by the cyclin-dependent kinase inhibitor AT7519 promotes the resolution of eosinophil-dominant allergic inflammation. PLoS One. 2011;6(9):e25683. doi: 10.1371/journal.pone.0025683. Epub 2011 Sep 30. PubMed PMID: 21984938; PubMed Central PMCID: PMC3184151.
4: Mahadevan D, Plummer R, Squires MS, Rensvold D, Kurtin S, Pretzinger C, Dragovich T, Adams J, Lock V, Smith DM, Von Hoff D, Calvert H. A phase I pharmacokinetic and pharmacodynamic study of AT7519, a cyclin-dependent kinase inhibitor in patients with refractory solid tumors. Ann Oncol. 2011 Sep;22(9):2137-43. doi: 10.1093/annonc/mdq734. Epub 2011 Feb 16. PubMed PMID: 21325451.
5: Squires MS, Cooke L, Lock V, Qi W, Lewis EJ, Thompson NT, Lyons JF, Mahadevan D. AT7519, a cyclin-dependent kinase inhibitor, exerts its effects by transcriptional inhibition in leukemia cell lines and patient samples. Mol Cancer Ther. 2010 Apr;9(4):920-8. doi: 10.1158/1535-7163.MCT-09-1071. Epub 2010 Mar 30. PubMed PMID: 20354122.
6: Santo L, Vallet S, Hideshima T, Cirstea D, Ikeda H, Pozzi S, Patel K, Okawa Y, Gorgun G, Perrone G, Calabrese E, Yule M, Squires M, Ladetto M, Boccadoro M, Richardson PG, Munshi NC, Anderson KC, Raje N. AT7519, A novel small molecule multi-cyclin-dependent kinase inhibitor, induces apoptosis in multiple myeloma via GSK-3beta activation and RNA polymerase II inhibition. Oncogene. 2010 Apr 22;29(16):2325-36. doi: 10.1038/onc.2009.510. Epub 2010 Jan 25. PubMed PMID: 20101221; PubMed Central PMCID: PMC3183744.
7: Squires MS, Feltell RE, Wallis NG, Lewis EJ, Smith DM, Cross DM, Lyons JF, Thompson NT. Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines. Mol Cancer Ther. 2009 Feb;8(2):324-32. doi: 10.1158/1535-7163.MCT-08-0890. Epub 2009 Jan 27. PubMed PMID: 19174555.
8: Wyatt PG, Woodhead AJ, Berdini V, Boulstridge JA, Carr MG, Cross DM, Davis DJ, Devine LA, Early TR, Feltell RE, Lewis EJ, McMenamin RL, Navarro EF, O'Brien MA, O'Reilly M, Reule M, Saxty G, Seavers LC, Smith DM, Squires MS, Trewartha G, Walker MT, Woolford AJ. Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design. J Med Chem. 2008 Aug 28;51(16):4986-99. doi: 10.1021/jm800382h. Epub 2008 Jul 26. PubMed PMID: 18656911.
