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MAT2A inhibitor Sale

目录号 : GC32925

MAT2A inhibitor 是一种甲硫氨酸腺苷转移酶 2A (MATA2) 抑制剂,IC50 小于 100 nM。

MAT2A inhibitor Chemical Structure

Cas No.:2201057-10-3

规格 价格 库存 购买数量
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500mg 待询 待询

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产品描述

MAT2A inhibitor is a methionine adenosyltransferase 2A (MATA2 ) inhibitor extracted from patent US20180079753, compound example 196 (4).

[1]. Konteatis Z, et al. Inhibitors of cellular metabolic processes. US20180079753.

Chemical Properties

Cas No. 2201057-10-3 SDF
Canonical SMILES O=C1C(C2=CC=C3N=C(C)SC3=C2)=C(NC4=NC=CC=C4)NC5=C(C6=CC=CC=C6)C(C7=CC=CC=C7)=NN15
分子式 C31H22N6OS 分子量 526.61
溶解度 DMSO : 5 mg/mL (9.49 mM) 储存条件 Store at -20°C
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1 mM 1.8989 mL 9.4947 mL 18.9894 mL
5 mM 0.3798 mL 1.8989 mL 3.7979 mL
10 mM 0.1899 mL 0.9495 mL 1.8989 mL
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Research Update

Discovery of AG-270, a First-in-Class Oral MAT2A inhibitor for the Treatment of Tumors with Homozygous MTAP Deletion

J Med Chem 2021 Apr 22;64(8):4430-4449.PMID:33829783DOI:10.1021/acs.jmedchem.0c01895.

The metabolic enzyme methionine adenosyltransferase 2A (MAT2A) was recently implicated as a synthetic lethal target in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene, which is adjacent to the CDKN2A tumor suppressor and codeleted with CDKN2A in approximately 15% of all cancers. Previous attempts to target MAT2A with small-molecule inhibitors identified cellular adaptations that blunted their efficacy. Here, we report the discovery of highly potent, selective, orally bioavailable MAT2A inhibitors that overcome these challenges. Fragment screening followed by iterative structure-guided design enabled >10 000-fold improvement in potency of a family of allosteric MAT2A inhibitors that are substrate noncompetitive and inhibit release of the product, S-adenosyl methionine (SAM), from the enzyme's active site. We demonstrate that potent MAT2A inhibitors substantially reduce SAM levels in cancer cells and selectively block proliferation of MTAP-null cells both in tissue culture and xenograft tumors. These data supported progressing AG-270 into current clinical studies (ClinicalTrials.gov NCT03435250).

Targeting S-adenosylmethionine biosynthesis with a novel allosteric inhibitor of Mat2A

Nat Chem Biol 2017 Jul;13(7):785-792.PMID:28553945DOI:10.1038/nchembio.2384.

S-Adenosyl-L-methionine (SAM) is an enzyme cofactor used in methyl transfer reactions and polyamine biosynthesis. The biosynthesis of SAM from ATP and L-methionine is performed by the methionine adenosyltransferase enzyme family (Mat; EC 2.5.1.6). Human methionine adenosyltransferase 2A (Mat2A), the extrahepatic isoform, is often deregulated in cancer. We identified a MAT2A inhibitor, PF-9366, that binds an allosteric site on Mat2A that overlaps with the binding site for the Mat2A regulator, Mat2B. Studies exploiting PF-9366 suggested a general mode of Mat2A allosteric regulation. Allosteric binding of PF-9366 or Mat2B altered the Mat2A active site, resulting in increased substrate affinity and decreased enzyme turnover. These data support a model whereby Mat2B functions as an inhibitor of Mat2A activity when methionine or SAM levels are high, yet functions as an activator of Mat2A when methionine or SAM levels are low. The ramification of Mat2A activity modulation in cancer cells is also described.

Fragment-Based Design of a Potent MAT2A inhibitor and in Vivo Evaluation in an MTAP Null Xenograft Model

J Med Chem 2021 May 27;64(10):6814-6826.PMID:33900758DOI:10.1021/acs.jmedchem.1c00067.

MAT2a is a methionine adenosyltransferase that synthesizes the essential metabolite S-adenosylmethionine (SAM) from methionine and ATP. Tumors bearing the co-deletion of p16 and MTAP genes have been shown to be sensitive to MAT2a inhibition, making it an attractive target for treatment of MTAP-deleted cancers. A fragment-based lead generation campaign identified weak but efficient hits binding in a known allosteric site. By use of structure-guided design and systematic SAR exploration, the hits were elaborated through a merging and growing strategy into an arylquinazolinone series of potent MAT2a inhibitors. The selected in vivo tool compound 28 reduced SAM-dependent methylation events in cells and inhibited proliferation of MTAP-null cells in vitro. In vivo studies showed that 28 was able to induce antitumor response in an MTAP knockout HCT116 xenograft model.

MAT2A as Key Regulator and Therapeutic Target in MLL r Leukemogenesis

Cancers (Basel) 2020 May 24;12(5):1342.PMID:32456310DOI:10.3390/cancers12051342.

Epigenetic dysregulation plays a pivotal role in mixed-lineage leukemia (MLL) pathogenesis, therefore serving as a suitable therapeutic target. S-adenosylmethionine (SAM) is the universal methyl donor in human cells and is synthesized by methionine adenosyltransferase 2A (MAT2A), which is deregulated in different cancer types. Here, we used our human CRISPR/Cas9-MLL-rearranged (CRISPR/Cas9-MLLr) leukemia model, faithfully mimicking MLLr patients' pathology with indefinite growth potential in vitro, to evaluate the unknown role of MAT2A. Comparable to publicly available patient data, we detected MAT2A to be significantly overexpressed in our CRISPR/Cas9-MLLr model compared to healthy controls. By using non-MLLr and MLLr cell lines and our model, we detected an MLLr-specific enhanced response to PF-9366, a new MAT2A inhibitor, and small interfering (si) RNA-mediated knockdown of MAT2A, by alteration of the proliferation, viability, differentiation, apoptosis, cell cycling, and histone methylation. Moreover, the combinational treatment of PF-9366 with chemotherapy or targeted therapies against the SAM-dependent methyltransferases, disruptor of telomeric silencing 1 like (DOT1L) and protein arginine methyltransferase 5 (PRMT5), revealed even more pronounced effects. In summary, we uncovered MAT2A as a key regulator in MLL leukemogenesis and its inhibition led to significant anti-leukemic effects. Therefore, our study paves the avenue for clinical application of PF-9366 to improve the treatment of poor prognosis MLLr leukemia.

Leveraging Structure-Based Drug Design to Identify Next-Generation MAT2A Inhibitors, Including Brain-Penetrant and Peripherally Efficacious Leads

J Med Chem 2022 Mar 24;65(6):4600-4615.PMID:35293760DOI:10.1021/acs.jmedchem.1c01595.

Inhibition of the S-adenosyl methionine (SAM)-producing metabolic enzyme, methionine adenosyltransferase 2A (MAT2A), has received significant interest in the field of medicinal chemistry due to its implication as a synthetic lethal target in cancers with the deletion of the methylthioadenosine phosphorylase (MTAP) gene. Here, we report the identification of novel MAT2A inhibitors with distinct in vivo properties that may enhance their utility in treating patients. Following a high-throughput screening, we successfully applied the structure-based design lessons from our first-in-class MAT2A inhibitor, AG-270, to rapidly redesign and optimize our initial hit into two new lead compounds: a brain-penetrant compound, AGI-41998, and a potent, but limited brain-penetrant compound, AGI-43192. We hope that the identification and first disclosure of brain-penetrant MAT2A inhibitors will create new opportunities to explore the potential therapeutic effects of SAM modulation in the central nervous system (CNS).