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AS-99 Sale

目录号 : GC62615

AS-99 是一流的、有效的、选择性的 ASH1L 组蛋白甲基转移酶抑制剂(IC50=0.79μ;M,Kd=0.89μ;M),具有抗白血病活性。 AS-99 阻断细胞增殖,诱导细胞凋亡和分化,下调 MLL 融合靶基因,并减少体内白血病负担。

AS-99 Chemical Structure

Cas No.:2323623-93-2

规格 价格 库存 购买数量
5 mg
¥5,220.00
现货
10 mg
¥8,820.00
现货

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产品描述

AS-99 is a first-in-class, potent and selective ASH1L histone methyltransferase inhibitor (IC50= 0.79 µM, Kd= 0.89 µM) with anti-leukemic activity. AS-99 blocks cell proliferation, induces apoptosis and differentiation, downregulates MLL fusion target genes, and reduces the leukemia burden in vivo[1].

AS-99 is tested against a panel of 20 histone methyltransferases, including NSD1, NSD2, NSD3, and SETD2. NO significant inhibition is observed at 50 µM of AS-99 on any of the tested histone methyltransferases, indicating over 100-fold selectivity towards ASH1L[1].AS-99 shows effect on the growth of the MLL leukemia cells (MV4;11, MOLM13, KOPN8, RS4;11) with the GI50 values ranging from 1.8 µM to 3.6 µM[1].AS-99 (1-8 µM; 7 days) also induces apoptosis in the MLL leukemia cells, but not in the K562 cells, as assessed by the quantification of the Annexin V positive cells[1].AS-99 suppresses MLL fusion driven transcriptional programs[1].

AS-99 (30 mg/kg; i.p.; q.d., treated for 14 consecutive days) reduces leukemia burden in mice[1].AS-99 is used for in vivo studies in mice, which reveals favorable exposure in plasma upon i.v. and i.p. administration (AUC = 9701 hr* ng/mL and 10,699 hr* ng/mL, respectively), suitable half-life (~5-6 h) and Cmax >10 µM[1].

[1]. David S. Rogawski, Jing Deng, Hao Li, Tomasz Cierpicki, Jolanta Grembecka, et al. Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity. Nat Commun. 2021 May 14;12(1):2792.

Chemical Properties

Cas No. 2323623-93-2 SDF
分子式 C27H30F3N5O3S2 分子量 593.68
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1 mM 1.6844 mL 8.422 mL 16.8441 mL
5 mM 0.3369 mL 1.6844 mL 3.3688 mL
10 mM 0.1684 mL 0.8422 mL 1.6844 mL
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Research Update

Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity

Nat Commun 2021 May 14;12(1):2792.PMID:33990599DOI:10.1038/s41467-021-23152-6.

ASH1L histone methyltransferase plays a crucial role in the pathogenesis of different diseases, including acute leukemia. While ASH1L represents an attractive drug target, developing ASH1L inhibitors is challenging, as the catalytic SET domain adapts an inactive conformation with autoinhibitory loop blocking the access to the active site. Here, by applying fragment-based screening followed by medicinal chemistry and a structure-based design, we developed first-in-class small molecule inhibitors of the ASH1L SET domain. The crystal structures of ASH1L-inhibitor complexes reveal compound binding to the autoinhibitory loop region in the SET domain. When tested in MLL leukemia models, our lead compound, AS-99, blocks cell proliferation, induces apoptosis and differentiation, downregulates MLL fusion target genes, and reduces the leukemia burden in vivo. This work validates the ASH1L SET domain as a druggable target and provides a chemical probe to further study the biological functions of ASH1L as well as to develop therapeutic agents.