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MSA-2 Sale

(Synonyms: 5,6-dimethoxy-γ-oxo-benzobthiophene-2-Butanoic Acid) 目录号 : GC61092

MSA-2是一种口服非核苷酸STING激动剂,对人的STING亚型WT和HAQ的EC50分别为8.3和24μM。MSA-2在同基因小鼠肿瘤模型中显示抗肿瘤活性,刺激肿瘤分泌干扰素-β,诱导肿瘤消退,具有持久的抗肿瘤免疫,并与抗PD-1协同作用。

MSA-2 Chemical Structure

Cas No.:129425-81-6

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产品描述

MSA-2, a potent and orally available non-nucleotide STING agonist, has EC50s of 8.3 and 24 μM for human STING isoforms WT and HAQ, respectively. MSA-2 shows antitumor activity and stimulates interferon-β secretion in tumors, induces tumor regression with durable antitumor immunity, and synergizes with anti-PD-1 in syngeneic mouse tumor models[1].

MSA-2 dosed via either PO or SC regimens achieved comparable exposure in both tumor and plasma. MSA-2 also exhibits dose-dependent antitumor activity when administered by IT, SC, or PO routes, and dosing regimens were identified that induced complete tumor regressions in 80 to 100% of treated animals[1].MSA-2 (PO: 60 mg/kg or SC: 50 mg/kg; single dose) that effectively inhibits tumor growth induced substantial elevations of IFN-β, interleukin-6 (IL-6), and TNF-α in tumor[1]. Animal Model: MC38 tumor-bearing C57BL6 mice[1]

MSA-2 是一种有效的口服非核苷酸 STING 激动剂,对人类 STING 亚型 WT 和 HAQ 的 EC50 分别为 8.3 和 24 μM。 MSA-2 显示出抗肿瘤活性并刺激肿瘤中的干扰素-β 分泌,诱导肿瘤消退并具有持久的抗肿瘤免疫力,并在同系小鼠肿瘤模型中与抗 PD-1 药物产生协同作用[1]。

通过 PO 或 SC 方案给药的 MSA-2 在肿瘤和血浆中的暴露量相当。当通过 IT、SC 或 PO 途径给药时,MSA-2 还表现出剂量依赖性抗肿瘤活性,并且确定了给药方案可在 80% 至 100% 的治疗动物中诱导肿瘤完全消退 [1]。MSA-2(PO:60 mg/kg 或 SC:50 mg/kg;单剂量)可有效抑制肿瘤生长,诱导肿瘤中 IFN-β、白介素-6 (IL-6) 和 TNF-α 显着升高[1]。动物模型:MC38荷瘤C57BL6小鼠[1]

[1]. Pan BS, et al. An orally available non-nucleotide STING agonist with antitumor activity. Science. 2020;369(6506):eaba6098.

Chemical Properties

Cas No. 129425-81-6 SDF
别名 5,6-dimethoxy-γ-oxo-benzobthiophene-2-Butanoic Acid
Canonical SMILES O=C(C1=CC(C(S1)=C2)=CC(OC)=C2OC)CCC(O)=O
分子式 C14H14O5S 分子量 294.32
溶解度 DMSO: 125 mg/mL (424.71 mM) 储存条件 4°C, protect from light
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Research Update

Combination of oral STING agonist MSA-2 and anti-TGF-β/PD-L1 bispecific antibody YM101: a novel immune cocktail therapy for non-inflamed tumors

J Hematol Oncol 2022 Oct 8;15(1):142.PMID:36209176DOI:10.1186/s13045-022-01363-8.

Background: Non-inflamed tumors, including immune-excluded and immune-desert tumors, are commonly resistant to anti-PD-1/PD-L1 (α-PD-1/PD-L1) therapy. Our previous study reported the potent antitumor activity of anti-TGF-β/PD-L1 bispecific antibody YM101 in immune-excluded tumors. However, YM101 had limited antitumor activity in immune-desert models. MSA-2 is a novel oral stimulator of interferon genes (STING) agonist, which activates the innate immune system and may synergize with YM101 in overcoming immunotherapy resistance. Methods: The dose-dependent effect of MSA-2 on STING signaling was determined by interferon-β level. The maturation and function of dendritic cell (DC) were measured by flow cytometry, RNA-seq, one-way mixed lymphocyte reaction (MLR), OVA peptide pulse, and cytokine/chemokine detection. The synergistic effect between MSA-2 and YM101 was assessed by one-way MLR. The macrophage activation was measured by flow cytometry and cytokine/chemokine detection. The in vivo antitumor activity of MSA-2 combined with YM101 was explored in syngeneic murine tumor models. After treatments, the alterations in the tumor microenvironment (TME) were detected by flow cytometry, immunohistochemistry staining, immunofluorescence staining, RNA-seq, and single-cell RNA-seq (scRNA-seq). Results: MSA-2 could promote the maturation and antigen presentation capability of murine DC. In the one-way MLR assay, MSA-2 synergized with YM101 in enhancing naive T cell activation. Moreover, MSA-2 stimulated the classical activation of macrophage, without significant influence on alternative activation. Further in vivo explorations showed that MSA-2 increased multiple proinflammatory cytokines and chemokines in the TME. MSA-2 combined with YM101 remarkedly retarded tumor growth in immune-excluded and immune-desert models, with superior antitumor activity to monotherapies. Flow cytometry, bulk RNA-seq, and scRNA-seq assays indicated that the combination therapy simultaneously boosted the innate and adaptive immunity, promoted antigen presentation, improved T cell migration and chemotaxis, and upregulated the numbers and activities of tumor-infiltrating lymphocytes. Conclusion: Our results demonstrate that MSA-2 synergizes with YM101 in boosting antitumor immunity. This immune cocktail therapy effectively overcomes immunotherapy resistance in immune-excluded and immune-desert models.

An orally available non-nucleotide STING agonist with antitumor activity

Science 2020 Aug 21;369(6506):eaba6098.PMID:32820094DOI:10.1126/science.aba6098.

Pharmacological activation of the STING (stimulator of interferon genes)-controlled innate immune pathway is a promising therapeutic strategy for cancer. Here we report the identification of MSA-2, an orally available non-nucleotide human STING agonist. In syngeneic mouse tumor models, subcutaneous and oral MSA-2 regimens were well tolerated and stimulated interferon-β secretion in tumors, induced tumor regression with durable antitumor immunity, and synergized with anti-PD-1 therapy. Experimental and theoretical analyses showed that MSA-2 exists as interconverting monomers and dimers in solution, but only dimers bind and activate STING. This model was validated by using synthetic covalent MSA-2 dimers, which were potent agonists. Cellular potency of MSA-2 increased upon extracellular acidification, which mimics the tumor microenvironment. These properties appear to underpin the favorable activity and tolerability profiles of effective systemic administration of MSA-2.

Genetic polymorphism of Babesia bovis merozoite surface antigens-2 (MSA-2) isolates from bovine blood and Rhipicephalus annulatus ticks in Israel

Vet Parasitol 2014 Sep 15;205(1-2):20-7.PMID:25149097DOI:10.1016/j.vetpar.2014.07.016.

This study demonstrated the genetic diversity among MSA-2c, MSA-2a1 and MSA-2b proteins of Babesia bovis isolates obtained from bovine blood and Rhipicephalus annulatus tick samples. The least identities that were observed among the deduced amino acid sequences of MSA-2c, MSA-2a1 and MSA-2b were 55, 63, and 71%, respectively. During the study four B. bovis calves, aged about 1 month, were found to be infected with virulent field strains and developed babesiosis. Probably, the calves had received insufficient antibodies, or the antibodies raised against the vaccine strain did not cross-protect against virulent field isolates. The complete MSA-2 locus from the Israeli B. bovis vaccine strain and two field isolates were characterized. Similarly to the Australian strains and isolates, the MSA-2 loci of the examined Israeli strain and isolates had only two MSA-2 genes - msa-2c and msa-2a/b - located between msa-2c and orfB. Several of the examined samples, contained different MSA-2 genotypes concurrently. No obvious geographical relationships among isolates from various regions of Israel were established. Moreover, in the phylogenetic analyses, the Israeli deduced MSA-2 amino acid sequences of the three examined genes were clustered together with sequences derived from other countries, proving that the MSA-2 gene sequences of B. bovis shared the same genetic characters worldwide. The present study clearly showed that the MSA-2 proteins of B. bovis isolates from Israel were genetically distinct from the vaccine strains. Thus, further research will be needed in order to understand the genetic diversity mechanisms of B. bovis, and the immunological responses of the infected animals.

Tumor factors stimulate lysosomal degradation of tumor antigens and undermine their cross-presentation in lung cancer

Nat Commun 2022 Nov 4;13(1):6623.PMID:36333297DOI:10.1038/s41467-022-34428-w.

Activities of dendritic cells (DCs) that present tumor antigens are often suppressed in tumors. Here we report that this suppression is induced by tumor microenvironment-derived factors, which activate the activating transcription factor-3 (ATF3) transcription factor and downregulate cholesterol 25-hydroxylase (CH25H). Loss of CH25H in antigen presenting cells isolated from human lung tumors is associated with tumor growth and lung cancer progression. Accordingly, mice lacking CH25H in DCs exhibit an accelerated tumor growth, decreased infiltration and impaired activation of intratumoral CD8+ T cells. These mice do not establish measurable long-term immunity against malignant cells that undergo chemotherapy-induced immunogenic cell death. Mechanistically, downregulation of CH25H stimulates membrane fusion between endo-phagosomes and lysosomes, accelerates lysosomal degradation and restricts cross-presentation of tumor antigens in the intratumoral DCs. Administration of STING agonist MSA-2 reduces the lysosomal activity in DCs, restores antigen cross presentation, and increases therapeutic efficacy of PD-1 blockade against tumour challenge in a CH25H-dependent manner. These studies highlight the importance of downregulation of CH25H in DCs for tumor immune evasion and resistance to therapy.

Allelic variants of the Plasmodium falciparum merozoite surface antigen 2 (MSA-2) in a geographically restricted area of Irian Jaya

Mol Biochem Parasitol 1994 Jan;63(1):13-21.PMID:8183312DOI:10.1016/0166-6851(94)90004-3.

Blood samples were collected from 12 residents of 4 villages in the Oksibil area of Irian Jaya. Eleven patients were positive for Plasmodium falciparum infection as evidenced by successful amplification of the MSA-2 gene by the polymerase chain reaction. Two patients showed evidence of infection by 2 strains of Plasmodium falciparum. All MSA-2 genes were completely sequenced and all could be assigned to one of the two major allelic families of MSA-2, however all MSA-2 gene sequences differed from previously described alleles. Five new allelic forms were identified, one of which was present in 8 of the 11 patients. Within small natural populations of P. falciparum, it appears that variation in MSA-2 approximates that seen world-wide. All samples were also analysed by hybridisation of amplified DNA to family specific probes and all samples hybridised to known probes. Our results demonstrate that there is a degree of microheterogeneity of MSA-2 that is undetectable by hybridisation studies alone.