YL-5092

Cell lines

MOLM-13, MV4-11, HL-60, THP-1, KG-1, U937, OCI-AML3 human acute myeloid leukemia (AML) cell lines, primary human AML specimens (CD34⁺ leukemia stem/progenitor cells), HEK293T cells transfected with EGFP-tagged YTHDC1, normal human umbilical cord blood (CB) CD34⁺ hematopoietic stem/progenitor (HSPC) cells

Preparation Method

AML cell lines and primary specimens were maintained in standard culture medium supplemented with 10% heat-inactivated fetal bovine serum (FBS) at 37°C, 5% CO₂. YL-5092 diluted to indicated working concentrations in culture medium for cell treatment.

Reaction Conditions

0.1–10μM, 72h

Applications

YL-5092 selectively engaged YTHDC1 in living AML cells without affecting other YTH family proteins or m⁶A reader proteins. YL-5092 blocked the binding of YTHDC1 to its m⁶A substrates (including MYC, FOXM1, GINS1, MCM2, MCM4, MCM5), reduced the stability and mRNA levels of these targets, and suppressed YTHDC1-mediated liquid-liquid phase separation and nuclear condensate formation in MV4-11 cells. YL-5092 dose-dependently inhibited the viability of all tested AML cell lines and primary AML specimens (half-maximum inhibitory concentration IC₅₀: 0.28–2.87μM), induced G₀/G₁ phase arrest, apoptosis and myeloid differentiation in AML cells, and suppressed the colony-forming capacity of CD34⁺ leukemia stem/progenitor cells, while exerting minimal impact on normal human umbilical cord blood CD34⁺ HSPCs and their lineage differentiation.

Animal models

C57BL/6J mice, MOLM-13-luciferase or U937-luciferase cell-derived xenograft (CDX) immunodeficient mice, four independent patient-derived xenograft (PDX) models of acute myeloid leukemia (AML), human umbilical cord blood (CB) CD34+ hematopoietic stem/progenitor cell (HSPC)-engrafted immunodeficient mice

Preparation Method

For CDX model establishment, MOLM-13 or U937 cells expressing luciferase were transplanted into immunodeficient mice via tail vein; YL-5092 (70mg/kg; i.p.; twice per day) was initiated 4 days post-transplant and continued for 18 consecutive days. For PDX model establishment, immunodeficient mice were transplanted with primary AML cells from four independent patients via tail vein; YL-5092 (70mg/kg; i.p.; twice per day) was initiated 10 days post-transplant and continued for 21 days; bone marrow (BM) cells isolated from primary PDX mice treated with vehicle or YL-5092 were serially transplanted into secondary recipient immunodeficient mice to evaluate leukemia stem cell (LSC) function. For combination efficacy test, YL-5092 (50mg/kg; i.p.; twice per day) was administered together with standard AML therapy venetoclax plus azacitidine (Ven/Aza) in CDX and PDX models.

Dosage form

50 or 70mg/kg; i.p.; twice per day for18 days

Applications

In CDX models, YL-5092 monotherapy significantly alleviated leukemia burden, reduced the proportion of human CD45⁺CD33⁺ leukemia cells in peripheral blood, spleen and bone marrow, downregulated the expression of YTHDC1 target genes (MYC, FOXM1, GINS1, MCM2, MCM4, MCM5) in BM-derived leukemia cells, and prolonged the overall survival of recipient mice. In PDX models YL-5092 monotherapy reduced leukemia burden in bone marrow across four PDX models with distinct genetic backgrounds, extended the survival of PDX-4 mice, and serial transplantation assays showed that YL-5092-treated primary PDX BM cells had markedly impaired leukemia reconstitution capacity in secondary recipients, indicating functional impairment of LSCs. In combination therapy settings, YL-5092 combined with Ven/Aza exerted stronger anti-leukemia efficacy and longer survival extension than either single agent in both CDX and PDX models.

References:
[1] Zhang H, Li Y, Zhao Y, et al. Small-molecule inhibition of YTHDC1 as a strategy against acute myeloid leukemia in mouse models. Sci Transl Med. 2026 Feb 4;18(835):eadu3137.