A novel small molecule menin-MLL inhibitor for …
SEM (MLL-AF4 ALL) 17 nM. KG-1 >4.5 µM • KO-539 shows good biochemical and cellular activity • KO-539 displays >50 fold selectivity over non -MLL fusion cell lines. Structure-based optimization. KO-539 as . Development. Candidate-7-6-5-4-3-2-1. 0. Fold Change (log2) Vehicle. KO539 50mpk qd. KO539 100mpk qd. HOXA9/HPRT1.
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Prepare Menin at 200 nM, MLL-w.t.-fluorescein at 25 nM, MLL-mutant-texas red at 50 nM, and 10 uM MLL-w.t. unlabeled mixture in FP buffer. 3. Prepare MLL-w.t.-fluorescein at 25 nM and MLL-mutant-texas red at 50 nM mixture in FP buffer. 3. Dispense 4 ul per well of reagent in step 1 in columns 2, 4 - 48 in a black 1536 well plate, dispense 4 ul ...
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MLL-rearranged (MLL1, KMT2A) leukemias are an aggressive clinical subgroup of AML and acute lymphoblastic leukemia (ALL) with poor clinical outcomes, particularly in the context of therapy-associated AML and …
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Chromosomal translocations targeting the mixed lineage leukemia (MLL) gene result in MLL fusion proteins that are found in aggressive human acute leukemias. ... ∼ 10 nM) through two motifs, MBM1 and MBM2 (menin binding motifs 1 and 2). These motifs are located within the N-terminal 43-amino acid fragment of MLL, and the MBM1 represents a high ...
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WhatsApp: +86 18221755073A Novel Small Molecule Menin-MLL Inhibitor for …
SEM (MLL-AF4 ALL) 17 nM KG-1 > 4.5 µM Dose Median SurvivalBenefit Vehicle -16.5days KO-539 25 mpk qd 20 days 3.5 days 50 mpk qd 26 days 9.5 days 100 mpk qd 47.5 days 31 days B. Human CD45+cell inhibition KO-539 extends survival in the aggressive systemicMOLM-13leukemiamodelinmice
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The association of MLL1 with Menin/LEDGF is particularly critical for the function of MLL fusions, but also affects wild-type MLL1 (4 ... achieves antitumor activity while sparing platelets. Nat Med (2013) 19:202–8. 10.1038/nm.3048 [Google Scholar] 228. Souers AJ. Phase I study of ABT-199 (GDC-0199) in patients with relapsed/refractory non ...
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Inhibition of the Menin (MEN1) and MLL (MLL1, KMT2A) interaction is a potential therapeutic strategy for MLL-rearranged (MLL-r) leukemia. Structure-based design yielded the …
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WhatsApp: +86 18221755073A Novel Small Molecule Menin-MLL Inhibitor for …
We describe KO-539, a menin-MLL inhibitor with optimized drug-like properties that demonstrates potential clinical utility in preclinical models of MLL leukemias. The compound is currently …
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The IC50 values of MI-538 in inhibiting the leukemia cell lines (MV-4-11) carrying MLL fusion reached 21 nM. Treatment with MI-538 led to a strong downregulated expression of MEIS1 and HOXA9 genes (Figure 2F). Meanwhile, MI-538 significantly reduced MV-4-11 tumor volume in vivo and did not cause obvious toxic symptoms, which significantly ...
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Menin inhibitor ziftomenib (KO-539) synergizes with drugs targeting chromatin regulation or apoptosis and sensitizes acute myeloid leukemia with MLL rearrangement or …
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Shilatifard's laboratory discovered that individual cells with the pediatric leukemia had extremely low levels of a protein produced by the wild-type MLL gene. Shilatifard and Liang reasoned if they could beef up the levels of the wild-type MLL protein, it would displace the mutated version that drives cancer, and it could cure leukemia.
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