AT-9283 free base | CAS#896466-76-5 | multikinase inhibitor

MedKoo Cat#: 200322 | Name: AT-9283 free base

Description:

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

AT-9283 is a small-molecule multi-targeted kinase inhibitor with potent bioactivity against Aurora A and B kinases, JAK2, JAK3, and Abl kinases. It exhibits IC₅₀ values of 3 nM for Aurora B, 21 nM for Aurora A, 1.2 nM for JAK2, 1.1 nM for JAK3, and approximately 3 nM for Abl (including the T315I mutant). In preclinical cancer models, AT-9283 induces polyploidy and apoptosis in tumor cells due to mitotic disruption from Aurora inhibition, and demonstrates antiproliferative effects across a range of hematologic malignancies and solid tumors. It has shown in vivo efficacy in xenograft models and entered early-phase clinical trials, though dose-limiting toxicities such as neutropenia were observed.

Chemical Structure

AT-9283 free base

CAS#896466-04-9 (free base)

Theoretical Analysis

MedKoo Cat#: 200322

Name: AT-9283 free base

CAS#: 896466-04-9 (free base)

Chemical Formula: C19H23N7O2

Exact Mass: 381.1913

Molecular Weight: 381.43

Elemental Analysis: C, 59.83; H, 6.08; N, 25.70; O, 8.39

Price and Availability

Size	Price	Availability
50mg	USD 550.00	2 Weeks
100mg	USD 950.00	2 Weeks
200mg	USD 1,650.00	2 Weeks

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Related CAS #

896466-61-8 (HCl) 896466-04-9 (free base) 896466-76-5 (lactate)

Synonym

AT9283; AT 9283; AT-9283; AT-9283 free base.

IUPAC/Chemical Name

1-cyclopropyl-3-(3-(5-(morpholinomethyl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazol-4-yl)urea

InChi Key

LOLPPWBBNUVNQZ-UHFFFAOYSA-N

InChi Code

InChI=1S/C19H23N7O2/c27-19(21-13-2-3-13)24-16-10-20-25-17(16)18-22-14-4-1-12(9-15(14)23-18)11-26-5-7-28-8-6-26/h1,4,9-10,13H,2-3,5-8,11H2,(H,20,25)(H,22,23)(H2,21,24,27)

SMILES Code

O=C(NC1=CNN=C1C2=NC3=CC(CN4CCOCC4)=CC=C3N2)NC5CC5

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, not in water

Shelf Life

>5 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

AT9283 has been investigated as monotherapy in patients with advanced solid tumors in two phase 1, open-label, dose-escalation trials at centers in the UK, USA and Canada. The two trials confirmed AT9283 is safe and well tolerated in patients with advanced solid malignancies. Oral bioavailability of AT9283 in humans has also been demonstrated. In conjunction with Cancer Research UK, Astex PharmaceuticalsÂ™ is also investigating the activity of single agent AT9283 in pediatric patients with solid tumors in a trial being conducted at multiple sites in the UK. AT9283 has been investigated in a phase 1/2 open-label, dose-escalation trial to assess the safety, tolerability and preliminary efficacy of AT9283 as monotherapy in patients with acute leukemia. The trial was conducted at centers in the USA. AT9283 is also being investigated in a phase 2 setting in a chemotherapy refractory, multiple myeloma patient population in a trial being sponsored by the NCIC Clinical Trials Group in Canada. An additional pediatric leukemia trial being sponsored by Cancer Research UK is due to begin during 2011. To learn more about the development status of this compound, please see the most recent Astex Pharmaceuticals presentations. AT9283 is wholly owned by Astex Pharmaceuticals, with a pending license to Montigen Pharmaceuticals, contigent on Montigen financing. (source: http://astx.com).

Product Data

Product Data

Instruction

View handling instruction

Biological target:

AT9283 is a multi-targeted kinase inhibitor with potent activity against Aurora A/B, JAK2/3, Abl (T315I) and Flt3 (IC50s ranging from 1 to 30 nM).

In vitro activity:

Consistent with previous studies that inhibition of Aurora A and/or Aurora B suppresses cell proliferation, AT9283 effectively inhibited the growth of these cells with IC50 values ranging from 0.11 to 0.85 μM (Table 1). It is also known that apoptosis is induced in a diverse of cancers after Auroras A or B inhibition. As expected, AT9283 induced apoptosis at a concentration of ≥0.1 μM, suggesting that induction of apoptosis is dose-dependent (Fig. 3a). These results were confirmed by demonstrating an increased level of cleaved PARP in treated Granta-519, SUDHL-6, RL and Raji cells (Fig. 3b). Similar results were achieved in Granta-4, Granta-22 and SUDHL-4 cells (data not shown). In addition, apoptosis occurred as early as 24 hr in RL and 48 hr in Granta-4 and SUDHL-6 cells (Fig. 3c) indicating apoptosis induction is in a time-dependent in different B-NHL subtypes. Together, the data demonstrate that Aurora inhibition with AT9283 leads to inhibition of proliferation and promotion of apoptosis in aggressive B-NHL cells. Reference: Int J Cancer. 2012 Jun 15;130(12):2997-3005. https://pubmed.ncbi.nlm.nih.gov/21796626/

In vivo activity:

As shown in Fig. 5B, in the group treated with 45 mg/kg IP once a day for 2 days a week for 4 weeks, tumor growth was inhibited compared to controls (p =0.018). TUNEL assays on tumor sections from treated versus control mice showed significantly increased apoptosis. Moreover IHC analysis of tumor taken from mice following administration of 2 cycles of AT9283 45 mg/kg 14 hours after drug administration confirmed decreased expression of phospho-Histone H3 and Aurora B in treated animals (Fig. 5E). blot analysis on tumor tissue showed decreased levels of pSTAT3, Aurora A and Aurora B (Fig. 5F). Using Kaplan-Meier and log-rank analysis, the median overall survival (OS) of animals treated with 45 mg/kg IP once a day for 2 days a week for 4 weeks was significantly prolonged (32 days versus 18 days respectively; p < 0.0001) (Fig. 5C). Importantly, treatment with AT9283 did not affect the body weight of the animals (Fig. 5D). Reference: Clin Cancer Res. 2011 May 15; 17(10): 3259–3271. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4163546/

	Solvent	mg/mL	mM
Solubility
	DMSO	68.7	180.03
	DMSO:PBS (pH 7.2) (1:1)	0.5	1.31
	DMF	30.0	78.65
	Ethanol	43.0	112.73

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 381.43 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. Takeda T, Tsubaki M, Genno S, Nemoto C, Onishi Y, Yamamoto Y, Imano M, Satou T, Nishida S. AT9283 exhibits antiproliferative effect on tyrosine kinase inhibitor‑sensitive and ‑resistant chronic myeloid leukemia cells by inhibition of Aurora A and Aurora B. Oncol Rep. 2020 Nov;44(5):2211-2218. doi: 10.3892/or.2020.7739. Epub 2020 Aug 18. PMID: 33000229. 2. Qi W, Liu X, Cooke LS, Persky DO, Miller TP, Squires M, Mahadevan D. AT9283, a novel aurora kinase inhibitor, suppresses tumor growth in aggressive B-cell lymphomas. Int J Cancer. 2012 Jun 15;130(12):2997-3005. doi: 10.1002/ijc.26324. Epub 2011 Nov 19. PMID: 21796626. 3. Moawad EY. Optimizing and predicting the in vivo activity of AT9283 as a monotherapy and in combination with paclitaxel. J Gastrointest Cancer. 2015 Dec;46(4):380-9. doi: 10.1007/s12029-015-9761-9. PMID: 26346504. 4. Santo L, Hideshima T, Cirstea D, Bandi M, Nelson EA, Gorgun G, Rodig S, Vallet S, Pozzi S, Patel K, Unitt C, Squires M, Hu Y, Chauhan D, Mahindra A, Munshi NC, Anderson KC, Raje N. Antimyeloma activity of a multitargeted kinase inhibitor, AT9283, via potent Aurora kinase and STAT3 inhibition either alone or in combination with lenalidomide. Clin Cancer Res. 2011 May 15;17(10):3259-71. doi: 10.1158/1078-0432.CCR-10-3012. Epub 2011 Mar 23. PMID: 21430070; PMCID: PMC4163546.

In vitro protocol:

In vivo protocol:

1. Moawad EY. Optimizing and predicting the in vivo activity of AT9283 as a monotherapy and in combination with paclitaxel. J Gastrointest Cancer. 2015 Dec;46(4):380-9. doi: 10.1007/s12029-015-9761-9. PMID: 26346504. 2. Santo L, Hideshima T, Cirstea D, Bandi M, Nelson EA, Gorgun G, Rodig S, Vallet S, Pozzi S, Patel K, Unitt C, Squires M, Hu Y, Chauhan D, Mahindra A, Munshi NC, Anderson KC, Raje N. Antimyeloma activity of a multitargeted kinase inhibitor, AT9283, via potent Aurora kinase and STAT3 inhibition either alone or in combination with lenalidomide. Clin Cancer Res. 2011 May 15;17(10):3259-71. doi: 10.1158/1078-0432.CCR-10-3012. Epub 2011 Mar 23. PMID: 21430070; PMCID: PMC4163546.

1: Podesta JE, Sugar R, Squires M, Linardopoulos S, Pearson AD, Moore AS. Adaptation of the plasma inhibitory activity assay to detect Aurora, ABL and FLT3 kinase inhibition by AT9283 in pediatric leukemia. Leuk Res. 2011 Sep;35(9):1273-5. Epub 2011 Jun 12. PubMed PMID: 21665275. 2: Santo L, Hideshima T, Cirstea D, Bandi M, Nelson EA, Gorgun G, Rodig S, Vallet S, Pozzi S, Patel K, Unitt C, Squires M, Hu Y, Chauhan D, Mahindra A, Munshi NC, Anderson KC, Raje N. Antimyeloma activity of a multitargeted kinase inhibitor, AT9283, via potent Aurora kinase and STAT3 inhibition either alone or in combination with lenalidomide. Clin Cancer Res. 2011 May 15;17(10):3259-71. Epub 2011 Mar 23. PubMed PMID: 21430070. 3: Kimura S. AT-9283, a small-molecule multi-targeted kinase inhibitor for the potential treatment of cancer. Curr Opin Investig Drugs. 2010 Dec;11(12):1442-9. Review. PubMed PMID: 21154126. 4: Tanaka R, Squires MS, Kimura S, Yokota A, Nagao R, Yamauchi T, Takeuchi M, Yao H, Reule M, Smyth T, Lyons JF, Thompson NT, Ashihara E, Ottmann OG, Maekawa T. Activity of the multitargeted kinase inhibitor, AT9283, in imatinib-resistant BCR-ABL-positive leukemic cells. Blood. 2010 Sep 23;116(12):2089-95. Epub 2010 Jun 14. PubMed PMID: 20548094. 5: Dawson MA, Curry JE, Barber K, Beer PA, Graham B, Lyons JF, Richardson CJ, Scott MA, Smyth T, Squires MS, Thompson NT, Green AR, Wallis NG. AT9283, a potent inhibitor of the Aurora kinases and Jak2, has therapeutic potential in myeloproliferative disorders. Br J Haematol. 2010 Jul;150(1):46-57. Epub 2010 May 7. PubMed PMID: 20507304. 6: Lok W, Klein RQ, Saif MW. Aurora kinase inhibitors as anti-cancer therapy. Anticancer Drugs. 2010 Apr;21(4):339-50. Review. PubMed PMID: 20016367. 7: Curry J, Angove H, Fazal L, Lyons J, Reule M, Thompson N, Wallis N. Aurora B kinase inhibition in mitosis: strategies for optimising the use of aurora kinase inhibitors such as AT9283. Cell Cycle. 2009 Jun 15;8(12):1921-9. Epub 2009 Jun 15. PubMed PMID: 19440047. 8: Pinel S, Barbault-Foucher S, Lott-Desroches MC, Astier A. [Inhibitors of aurora kinases]. Ann Pharm Fr. 2009 Mar;67(2):69-77. Epub 2009 Feb 23. Review. French. PubMed PMID: 19298889. 9: Howard S, Berdini V, Boulstridge JA, Carr MG, Cross DM, Curry J, Devine LA, Early TR, Fazal L, Gill AL, Heathcote M, Maman S, Matthews JE, McMenamin RL, Navarro EF, O'Brien MA, O'Reilly M, Rees DC, Reule M, Tisi D, Williams G, Vinković M, Wyatt PG. Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity. J Med Chem. 2009 Jan 22;52(2):379-88. PubMed PMID: 19143567. 10: BayÃ©s M, Rabasseda X. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2008 Jan-Feb;30(1):67-99. PubMed PMID: 18389098.