AS-99 是首创的、有效的、选择性ASH1L组蛋白甲基转移酶抑制剂 (IC50= 0.79 μM，Kd= 0.89 μM)，并具有抗白血病活性。AS-99 阻断细胞增殖，诱导细胞凋亡 (apoptosis) 和细胞分化，下调 MLL 融合靶基因，减少体内白血病负担。
| 生物活性 | AS-99 is a first-in-class, potent, and selectiveASH1Lhistone methyltransferaseinhibitor (IC50= 0.79 μM,Kd= 0.89 μM) with anti-leukemic activity. AS-99 blocks cell proliferation, inducesapoptosisand differentiation, downregulates MLL fusion target genes, and reduces the leukemia burden in vivo[1]. |
| IC50& Target | 0.79 μM (ASH1L histone methyltransferase)[1] |
体外研究
(In Vitro) | 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 a several fold weaker effect on the proliferation of leukemia cells withoutMLL1translocations, such as SET2 and K562, with no or limited effects at 10 μM or higher concentrations[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 results in a reduced number of H3K36me2 peaks when compared to the DMSO-treated cells[1].
RT-PCR[1] | Cell Line: | MOLM13 cells | | Concentration: | 2-6 μM | | Incubation Time: | 7 days | | Result: | Led to a dose-dependent downregulation of canonical MLL fusion target genes required for leukemogenesis including MEF2C, DLX2, FLT3, and HOXA9. |
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体内研究
(In Vivo) | 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].
| Animal Model: | 8- to 10-week old female NSG mice (bearing MV4;11 cells)[1] | | Dosage: | 30 mg/kg | | Administration: | I.p.; q.d., treated for 14 consecutive days | | Result: | Reduced the leukemia burden in the xenotransplantation mouse model of MLL leukemia without affecting blood counts in normal mice. |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | Please store the product under the recommended conditions in the Certificate of Analysis. |
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