AS-99 TFA

• CAT Number: I045288
• Molecular Formula: C29H31F6N5O5S2
• Molecular Weight: 707.71
• Purity: ≥95%
• Synonyms: N-[[3-(3-carbamothioylphenyl)-1-[1-(trifluoromethylsulfonyl)piperidin-4-yl]indol-6-yl]methyl]-1-methylazetidine-3-carboxamide;2,2,2-trifluoroacetic acid
• InChI: InChI=1S/C27H30F3N5O3S2.C2HF3O2/c1-33-14-20(15-33)26(36)32-13-17-5-6-22-23(18-3-2-4-19(12-18)25(31)39)16-35(24(22)11-17)21-7-9-34(10-8-21)40(37,38)27(28,29)30;3-2(4,5)1(6)7/h2-6,11-12,16,20-21H,7-10,13-15H2,1H3,(H2,31,39)(H,32,36);(H,6,7)
• InChIKey: ITRLRZWBIQCNTH-UHFFFAOYSA-N
• SMILES: CN1CC(C1)C(=O)NCC2=CC3=C(C=C2)C(=CN3C4CCN(CC4)S(=O)(=O)C(F)(F)F)C5=CC(=CC=C5)C(=S)N.C(=O)(C(F)(F)F)O

AS-99 TFA 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 TFA blocks cell proliferation, induces apoptosis and differentiation, downregulates MLL fusion target genes, and reduces the leukemia burden in vivo[1].
AS-99 TFA 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 TFA 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 without MLL1 translocations, such as SET2 and K562, with no or limited effects at 10 µM or higher concentrations[1].
AS-99 (1-8 µM; 7 days) TFA 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 TFA 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].
AS-99 (30 mg/kg; i.p.; q.d., treated for 14 consecutive days) TFA reduces leukemia burden in mice[1].
AS-99 TFA 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].

Reference

[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.
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