1352226-88-0

Basic information

• Product Name: AZD6738
• Synonyms: AZD6738;AZD-6738;4-[4-[1-[[S(R)]-S-Methylsulfonimidoyl]cyclopropyl]-6-[(3R)-3-methyl-4-morpholinyl]-2-pyrimidinyl]-1H-pyrrolo[2,3-b]pyridine;AZD6738(AZD-6738);(R)-imino(methyl)(1-(6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)cyclopropyl)-l6-sulfanone;(3R)-3-Methyl-4-(6-((2R)-2-((R)-S-methylsulfonimidoyl)cyclopropyl)-2-(1H-pyrrolo[2,3-b]pyridin;EOS-61602;(R)-3-methyl-4-(6-(1-((R)-S-methylsulfonimidoyl)cyclopropyl)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine
• CAS NO: 1352226-88-0
• Molecular Formula: C₂₀H₂₄N₆O₂S
• Molecular Weight: 412.52
• EINECS: 1592732-453-0
• Mol File: 1352226-88-0.mol
• Article Data: 6

Chemical Properties

• Appearance: /
• Density: 1.52±0.1 g/cm3(Predicted)
• Storage Temp.: Hygroscopic, -20°C Freezer, Under inert atmosphere
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 12.53±0.40(Predicted)
• CAS DataBase Reference: AZD6738(CAS DataBase Reference)
• NIST Chemistry Reference: AZD6738(1352226-88-0)
• EPA Substance Registry System: AZD6738(1352226-88-0)

Safety Data

• Hazardous Substances Data: 1352226-88-0(Hazardous Substances Data)

Usage

Description

AZD6738 is an orally bioavailable inhibitor of the serine/threonine protein kinase ataxia telangiectasia mutated (ATM) and Rad3-related (ATR). It has been shown to inhibit ATR substrate Chk1 Ser345 phosphorylation in cells and effectively reduce tumor growth in various xenograft models. AZD6738 is particularly effective in inhibiting the proliferation of solid and hematological cell lines and demonstrates synergistic cell-killing activity when used in combination with DNA damaging chemotherapy agents or ionizing radiation.

Uses

Used in Anticancer Applications:
AZD6738 is used as an antineoplastic agent for the inhibition of ATR activity, which plays a key role in DNA repair, cell cycle progression, and survival in various cancer cell types. By blocking the downstream phosphorylation of the serine/threonine protein kinase CHK1, AZD6738 prevents ATR-mediated signaling, leading to the inhibition of DNA damage checkpoint activation, disruption of DNA damage repair, and the induction of tumor cell apoptosis. Additionally, AZD6738 sensitizes tumor cells to chemoand radiotherapy, enhancing the efficacy of these treatments.
Used in Drug Development:
AZD6738 is used as a research tool for the development of novel cancer therapies. Its ability to inhibit ATR and ATM kinases makes it a valuable compound for studying the mechanisms of DNA repair and cell cycle regulation in cancer cells. Furthermore, its synergistic effects with DNA damaging chemotherapy agents and ionizing radiation provide insights into potential combination therapies for improved cancer treatment outcomes.

Enzyme inhibitor

This orally active, and selective ATR kinase inhibitor (FW = 412.51 g/mol; CAS 1352226-88-0; Solubility: 80 mg/mL DMSO; < 1 mg/mL H2O) targets Ataxia Telangiectasia/Rad3-related kinase (IC50 = 1 nM), a serine/threonine protein kinase that activates checkpoint signaling upon genotoxic stresses (e.g., ionizing radiation, ultraviolet light, or replication stalling), thereby serving as a DNA damage sensor. In a model consisting of primary human Chronic Myelogenous Leukemia (CL) cells with biallelic TP53 or ATM inactivation xenotransplanted into NOD/Shi scid/IL-2Rγ mice, AZD6738 provides potent and specific inhibition of ATR signalling with compensatory activation of ATM/p53 pathway in cycling CLL cells in the presence of genotoxic stress. In p53 or ATM defective cells, AZD6738 treatment results in replication fork stalls and accumulation of unrepaired DNA damage, as evidenced by γH2AX and 53BP1 foci formation, carried through into mitosis and resulting in cell death by mitotic catastrophe. AZD6738 displays selective cytotoxicity towards ATM- or p53-deficient CLL cells. AZD6738 also potentiates cisplatin and gemcitabine cytotoxicity in Non-Small-Cell Lung Carcinoma (NSCLC) cell lines with intact ATM kinase signaling. It also potently synergizes with cisplatin in ATM-deficient NSCLC cells. When used in combination, cisplatin and AZD6738 resolve ATM-deficient lung cancer xenografts.

references

[1]. choi my, fecteau jf, brown j, et al. induction of proliferation sensitizes chronic lymphocytic leukemia cells to apoptosis mediated by the atr inhibitor azd6738. cancer research, 2014, 74(19 supplement): 5485-5485.[2]. checkley s, maccallum l, yates j, et al. bridging the gap between in vitro and in vivo: dose and schedule predictions for the atr inhibitor azd6738. scientific reports, 2015, 5.[3]. guichard sm, brown e, odedra r, et al. the pre-clinical in vitro and in vivo activity of azd6738: a potent and selective inhibitor of atr kinase. cancer research, 2013, 73(8 supplement): 3343-3343.

Upstream product

• 98485-43-9 1-Methylmercapto-cyclopropan-carbonsaeure-⁽¹⁾-methylester 
• 942919-26-8 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine 
• 916176-50-6 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine 
• 1352412-35-1 (1-[2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl]cyclopropyl)(imino)methyl-lambda6-sulfanone 
• 1352232-89-3 (3R)-3-methyl-4-(6-(1-((R)-S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine 
• 1352227-19-0 N-[({2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}methyl)(R-methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide 
• 1352227-17-8 (R)-4-(2-chloro-6-((S)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine 
• 1352227-16-7 (3R)-4-[2-chloro-6-[[(R)-methylsulfinyl]methyl]pyrimidin-4-yl]-3-methyl-morpholine 
• 1352232-88-2 (3R)-3-methyl-4-(6-(1-(S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidin-4-yl)morpholine 
• 1352227-18-9 (3R)-4-(2-chloro-6-[(methylsulfinyl)methyl]-4-pyrimidinyl)-3-methylmorpholine 
• 1352227-15-6 (3R)-4-[2-chloro-6-[(methylsulfanyl)methyl]pyrimidin-4-yl]-3-methylmorpholine 
• 1352280-97-7 imino(methyl)[1-[6-[(3R)-3-methylmorpholin-4-yl]-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl]cyclopropyl]oxo-λ6-sulfane 
• 1246761-84-1 (1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid 
• 1352282-87-1 (3R)-4-(2-chloro-6-(1-((R)-S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine 

Relevant articles and documents

Development and Scale-Up of an Improved Manufacturing Route to the ATR Inhibitor Ceralasertib

Ceralasertib is currently being evaluated in multiple phase I/II clinical trials for the treatment of cancer. Its structure, comprising a pyrimidine core decorated with a chiral morpholine, a cyclopropyl sulfoximine and an azaindole, makes it a challenging molecule to synthesize on a large scale. Several features of the medicinal chemistry and early development route make it unsuitable for the long-term commercial manufacture of the active pharmaceutical ingredient. We describe the investigation and development of a new and improved route which introduces the cyclopropyl moiety in a novel process from methyl 2,4-dibromobutyrate. Following construction of the pyrimidine ring, large-scale chlorination with phosphoryl chloride was performed with a safe and robust work-up. An SNAr reaction required an innovative work-up to remove the unwanted regio-isomer, and then a Baeyer-Villiger monooxygenase enzyme was used to enable asymmetric sulfur oxidation to a sulfoxide. A safe and scalable metal-free sulfoximine formation was developed, and then optimization of a Suzuki reaction enabled the manufacture of high-quality ceralasertib with excellent control of impurities and an overall yield of 16%.

Synthesis method of pyrimidine heterocyclic ring-containing antitumor medicine molecule AZD6738

The invention belongs to the technical field of heterocyclic chemistry, particularly relates to a heterocyclic anti-tumor chemical medicine, and more particularly relates to a synthesis method of pyrimidine heterocyclic ring-containing antitumor medicine molecule AZD6738. A chiral ligand induced asymmetric oxidation method is used, chiral ligands are combined with cheap oxidizing agents (such as hydrogen peroxide) to oxidize dimethyl sulfide to prepare chiral sulfoxide, conversion of the chiral sulfoxide is efficiently achieved, a chiral sulfoxide compound 7 for the AZD6738 is prepared, and then the final product AZD6738 is prepared through an intermittent reaction. Besides, the AZD6738 is prepared by adopting a fluid chemical method, the total yield of total synthesis of the AZD6738 is remarkably improved compared with that of an intermittent reaction, and the method is suitable for industrial production.

Discovery and Characterization of AZD6738, a Potent Inhibitor of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Kinase with Application as an Anticancer Agent

The kinase ataxia telangiectasia mutated and rad3 related (ATR) is a key regulator of the DNA-damage response and the apical kinase which orchestrates the cellular processes that repair stalled replication forks (replication stress) and associated DNA double-strand breaks. Inhibition of repair pathways mediated by ATR in a context where alternative pathways are less active is expected to aid clinical response by increasing replication stress. Here we describe the development of the clinical candidate 2 (AZD6738), a potent and selective sulfoximine morpholinopyrimidine ATR inhibitor with excellent preclinical physicochemical and pharmacokinetic (PK) characteristics. Compound 2 was developed improving aqueous solubility and eliminating CYP3A4 time-dependent inhibition starting from the earlier described inhibitor 1 (AZ20). The clinical candidate 2 has favorable human PK suitable for once or twice daily dosing and achieves biologically effective exposure at moderate doses. Compound 2 is currently being tested in multiple phase I/II trials as an anticancer agent.