AT-7519 free base | CAS# 844442-38-2 | Multi-cyclin-dependent kinase Inhibitor

MedKoo Cat#: 573534 | Name: AT-7519 free base

Description:

WARNING: This product is for research use only, not for human or veterinary use.

AT-7519 free base is a drug that acts as a multi-cyclin-dependent kinase inhibitor for Cdk1/cyclin B, Cdk2/Cyclin A, Cdk3/Cyclin E, Cdk4/Cyclin D1, Cdk5/p35, and Cdk6/Cyclin D3. AT7519 is an ATP competitive Cdk inhibitor but is inactive against all non-Cdk kinases with the exception of GSK3β. AT7519 shows potent antiproliferative activity in a variety of human tumor cell lines such as SW620. AT7519 induces activation of GSK-3β by down-regulating GSK-3β phosphorylation, which also contributes to AT7519 induced apoptosis independent of the inhibition of transcription.

Chemical Structure

AT-7519 free base

CAS#844442-38-2 (free base)

Theoretical Analysis

MedKoo Cat#: 573534

Name: AT-7519 free base

CAS#: 844442-38-2 (free base)

Chemical Formula: C16H17Cl2N5O2

Exact Mass: 381.0759

Molecular Weight: 382.24

Elemental Analysis: C, 50.28; H, 4.48; Cl, 18.55; N, 18.32; O, 8.37

Price and Availability

Size	Price	Availability
50mg	USD 450.00	2 Weeks
100mg	USD 750.00	2 Weeks
200mg	USD 1,250.00	2 Weeks
500mg	USD 2,650.00	2 Weeks
1g	USD 3,850.00	2 Weeks
2g	USD 6,450.00	2 Weeks

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Related CAS #

902135-91-5 (HCl) 844442-38-2 (free base) 902135-89-1(methanesulfonate) 1431697-85-6 (trifluoroacetate)

Synonym

AT-7519, AT7519, AT 7519, AT-7519 free base

IUPAC/Chemical Name

4-(2,6-Dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide

InChi Key

OVPNQJVDAFNBDN-UHFFFAOYSA-N

InChi Code

1S/C16H17Cl2N5O2/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)

SMILES Code

c1cc(c(c(c1)Cl)C(=O)Nc2c[nH]nc2C(=O)NC3CCNCC3)Cl

Appearance

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

Shelf Life

>3 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

Cdk1/cyclin B (IC50 = 210 nM) Cdk2/Cyclin A (IC50 = 47 nM) Cdk3/Cyclin E (IC50 = 360 nM) Cdk4/Cyclin D1 (IC50 = 100 nM) Cdk5/p35 (IC50 = 13 nM) Cdk6/Cyclin D3 (IC50 = 170 nM) GSK3β (IC50 = 89 nM)

Product Data

Product Data

Instruction

View handling instruction

Biological target:

AT7519 as a potent 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	mg/mL	mM
Solubility
	DMSO	37.5	98.11

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 382.24 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:

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: Komiyama T, Kihara H, Hirose K, Yoshimoto R, Shigematsu H. AT-1015, a novel serotonin2A receptor antagonist, improves resaturation of exercised ischemic muscle in hypercholesterolemic rabbits. J Vasc Surg. 2004 Mar;39(3):661-7. PubMed PMID: 14981464. 2: Rashid M, Watanabe M, Nakazawa M, Nagatomo T. AT-1015, a newly synthesized 5-HT2 receptor antagonist, dissociates slowly from the 5-HT2 receptor sites in rabbit cerebral cortex membrane. J Pharm Pharmacol. 2002 Aug;54(8):1123-8. PubMed PMID: 12195828. 3: Rashid M, Watanabe M, Nakazawa M, Nakamura T, Hattori K, Nagatom T. Assessment of affinity and dissociation ability of a newly synthesized 5-HT2 antagonist, AT-1015: comparison with other 5-HT2 antagonists. Jpn J Pharmacol. 2001 Nov;87(3):189-94. PubMed PMID: 11885967. 4: Kihara H, Koganei H, Hirose K, Yamamoto H, Yoshimoto R. Antithrombotic activity of AT-1015, a potent 5-HT(2A) receptor antagonist, in rat arterial thrombosis model and its effect on bleeding time. Eur J Pharmacol. 2001 Dec 21;433(2-3):157-62. PubMed PMID: 11755147. 5: Kihara H, Hirose K, Koganei H, Sasaki N, Yamamoto H, Kimura A, Nishimori T, Shoji M, Yoshimoto R. AT-1015, a novel serotonin (5-HT)2 receptor antagonist, blocks vascular and platelet 5-HT2A receptors and prevents the laurate-induced peripheral vascular lesion in rats. J Cardiovasc Pharmacol. 2000 Apr;35(4):523-30. PubMed PMID: 10774780.