AZD3229 tosylate | CAS#2248003-71-4 | pan-KIT inhibitor

MedKoo Cat#: 462474 | Name: AZD3229 tosylate

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Description:

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

AZD3229 is a potent pan-KIT mutant inhibitor for the treatment of gastrointestinal stromal tumors. AZD3229 demonstrates potent single digit nM growth inhibition across a broad cell panel, with good margin to KDR-driven effects. Selectivity over KDR can be rationalised predominantly by the interaction of water molecules with the protein and ligand in the active site and its kinome selectivity is similar to the best of the approved GIST agents. AZD3229 demonstrates excellent cross-species pharmacokinetics, shows strong pharmacodynamic inhibition of target, and is active in several in vivo models of GIST.

Chemical Structure

AZD3229 tosylate

CAS#2248003-71-4 (tosylate)

Theoretical Analysis

MedKoo Cat#: 462474

Name: AZD3229 tosylate

CAS#: 2248003-71-4 (tosylate)

Chemical Formula: C31H34FN7O6S

Exact Mass: 0.0000

Molecular Weight: 651.71

Elemental Analysis: C, 57.13; H, 5.26; F, 2.92; N, 15.04; O, 14.73; S, 4.92

Price and Availability

Size	Price	Availability	Quantity
5mg	USD 400.00	2 Weeks
10mg	USD 700.00	2 Weeks

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Related CAS #

2248003-71-4 (tosylate) 2248003-60-1 (free base)

Synonym

AZD3229 Tosylate; AZD-3229 Tosylate; AZD 3229 Tosylate

IUPAC/Chemical Name

N-(4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide 4-methylbenzenesulfonate

InChi Key

AWHHAHZPRULJMA-UHFFFAOYSA-N

InChi Code

InChI=1S/C24H26FN7O3.C7H8O3S/c1-15(2)21-12-32(31-30-21)13-22(33)28-16-4-6-17(7-5-16)29-24-23-19(25)10-18(35-9-8-34-3)11-20(23)26-14-27-24;1-6-2-4-7(5-3-6)11(8,9)10/h4-7,10-12,14-15H,8-9,13H2,1-3H3,(H,28,33)(H,26,27,29);2-5H,1H3,(H,8,9,10)

SMILES Code

COCCOC1=CC(F)=C2C(N=CN=C2NC3=CC=C(NC(CN4C=C(C(C)C)N=N4)=O)C=C3)=C1.CC5=CC=C(S(O)(=O)=O)C=C5

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

AZD3229 is 15 to 60 times more potent than imatinib in inhibiting KIT primary mutations and has low nanomolar activity against a wide spectrum of secondary mutations. AZD3229 causes durable inhibition of KIT signaling in patient-derived xenograft (PDX) models of GIST, leading to tumor regressions at doses that showed no changes in arterial blood pressure (BP) in rat telemetry studies. AZD3229 has a superior potency and selectivity profile to standard of care (SoC) agents-imatinib, sunitinib, and regorafenib, as well as investigational agents, avapritinib (BLU-285) and ripretinib (DCC-2618). AZD3229 has the potential to be a best-in-class inhibitor for clinically relevant KIT/PDGFRα mutations in GIST.

Product Data

Product Data

Instruction

View handling instruction

Biological target:

AZD3229 Tosylate is a potent pan-KIT mutant inhibitor for the treatment of gastrointestinal stromal tumors.

In vitro activity:

AZD3229 inhibited growth of these Ba/F3 cell lines with GI50 values of 2.7, 3.1, and 0.7 nM, respectively, with 26- to 64-fold increase in potency relative to imatinib (Fig. 2A). AZD3229 was 2- to 10-fold more potent than sunitinib and 30- to 50-fold more potent than regorafenib. AZD3229 was also 8- to 110-fold more potent than avapritinib and ripretinib in inhibiting KIT primary mutations. Reference: Sci Transl Med. 2020 Apr 29;12(541):eaaz2481. https://pubmed.ncbi.nlm.nih.gov/32350132/

In vivo activity:

In the four in vivo mouse models explored here, AZD3229 drives rapid and extensive decrease in levels of phosphorylated KIT in a concentration-dependent manner following a single oral dose of AZD3229 (Fig. 1; Supplementary Table S4). The observed maximal inhibition of phosphorylation of KIT relative to baseline occurs around the time of maximum AZD3229 (2–3 hours), and the level of pKIT recovers to baseline levels tracking the PK profile. In the GIST430/V654 (KIT exon 11 del 560-578/V654A) and HGiXF-106 (KIT exon 11 del 557-558/V654A) models, the level of KIT phosphorylation reaches above the vehicle baseline at the 24-hour time point, but this was considered within assay variability, rather than representing significant PD rebound above baseline. The effects on KIT phosphorylation levels after 3 days of twice daily oral dosing was also investigated (except in the Ba/F3 allograft model), and the response mirrored that seen after a single dose, which was evidence that there was no time-dependent change for the inhibition of phosphorylation of KIT. Reference: Clin Cancer Res. 2020 Jul 15;26(14):3751-3759. https://pubmed.ncbi.nlm.nih.gov/32220888/

	Solvent	mg/mL	mM	comments
Solubility
	DMSO	100.0	153.44

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 651.71 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. Banks E, Grondine M, Bhavsar D, Barry E, Kettle JG, Reddy VP, Brown C, Wang H, Mettetal JT, Collins T, Adeyemi O, Overman R, Lawson D, Harmer AR, Reimer C, Drew L, Packer MJ, Cosulich S, Jones RD, Shao W, Wilson D, Guichard S, Fawell S, Anjum R. Discovery and pharmacological characterization of AZD3229, a potent KIT/PDGFRα inhibitor for treatment of gastrointestinal stromal tumors. Sci Transl Med. 2020 Apr 29;12(541):eaaz2481. doi: 10.1126/scitranslmed.aaz2481. PMID: 32350132. 2. Kettle JG, Anjum R, Barry E, Bhavsar D, Brown C, Boyd S, Campbell A, Goldberg K, Grondine M, Guichard S, Hardy CJ, Hunt T, Jones RDO, Li X, Moleva O, Ogg D, Overman RC, Packer MJ, Pearson S, Schimpl M, Shao W, Smith A, Smith JM, Stead D, Stokes S, Tucker M, Ye Y. Discovery of N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1 H-1,2,3-triazol-1-yl]acetamide (AZD3229), a Potent Pan-KIT Mutant Inhibitor for the Treatment of Gastrointestinal Stromal Tumors. J Med Chem. 2018 Oct 11;61(19):8797-8810. doi: 10.1021/acs.jmedchem.8b00938. Epub 2018 Sep 24. PMID: 30204441. 3. Pilla Reddy V, Anjum R, Grondine M, Smith A, Bhavsar D, Barry E, Guichard SM, Shao W, Kettle JG, Brown C, Banks E, Jones RDO. The Pharmacokinetic-Pharmacodynamic (PKPD) Relationships of AZD3229, a Novel and Selective Inhibitor of KIT, in a Range of Mouse Xenograft Models of GIST. Clin Cancer Res. 2020 Jul 15;26(14):3751-3759. doi: 10.1158/1078-0432.CCR-19-2848. Epub 2020 Mar 27. PMID: 32220888.

In vitro protocol:

In vivo protocol:

1: Kettle JG, Anjum R, Barry E, Bhavsar D, Brown C, Boyd S, Campbell A, Goldberg K, Grondine M, Guichard S, Hardy CJ, Hunt T, Jones RDO, Li X, Moleva O, Ogg D, Overman RC, Packer MJ, Pearson S, Schimpl M, Shao W, Smith A, Smith JM, Stead D, Stokes S, Tucker M, Ye Y. Discovery of N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinaz olin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1 H-1,2,3-triazol-1-yl]acetamide (AZD3229), a Potent Pan-KIT Mutant Inhibitor for the Treatment of Gastrointestinal Stromal Tumors. J Med Chem. 2018 Oct 11;61(19):8797-8810. doi: 10.1021/acs.jmedchem.8b00938. Epub 2018 Sep 24. PMID: 30204441. 2: Banks E, Grondine M, Bhavsar D, Barry E, Kettle JG, Reddy VP, Brown C, Wang H, Mettetal JT, Collins T, Adeyemi O, Overman R, Lawson D, Harmer AR, Reimer C, Drew L, Packer MJ, Cosulich S, Jones RD, Shao W, Wilson D, Guichard S, Fawell S, Anjum R. Discovery and pharmacological characterization of AZD3229, a potent KIT/PDGFRα inhibitor for treatment of gastrointestinal stromal tumors. Sci Transl Med. 2020 Apr 29;12(541):eaaz2481. doi: 10.1126/scitranslmed.aaz2481. PMID: 32350132. 3: Pilla Reddy V, Anjum R, Grondine M, Smith A, Bhavsar D, Barry E, Guichard SM, Shao W, Kettle JG, Brown C, Banks E, Jones RDO. The Pharmacokinetic- Pharmacodynamic (PKPD) Relationships of AZD3229, a Novel and Selective Inhibitor of KIT, in a Range of Mouse Xenograft Models of GIST. Clin Cancer Res. 2020 Jul 15;26(14):3751-3759. doi: 10.1158/1078-0432.CCR-19-2848. Epub 2020 Mar 27. PMID: 32220888.