XY0206 targets FLT3-dependent resistance states in acute myeloid leukemia
Long Shen, Yang Yang, Chenghua Xu, Bo Jiang, Xiaoxiao Duan, Xianfeng Shao, Simeng Li, Siyi Liu, Chao Huang, Lin Song, Mingyuan Sun, Jinting Fan, Ning Wang, Dong Zhang, Youyang Fang, Lichun Kang, Yajun Jiang, Mingming Niu, Junyuan Qi, Tao Cheng, Hong Wang
Long Shen, Yang Yang, Chenghua Xu, Bo Jiang, Xiaoxiao Duan, Xianfeng Shao, Simeng Li, Siyi Liu, Chao Huang, Lin Song, Mingyuan Sun, Jinting Fan, Ning Wang, Dong Zhang, Youyang Fang, Lichun Kang, Yajun Jiang, Mingming Niu, Junyuan Qi, Tao Cheng, Hong Wang
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Research Article Cell biology Clinical Research Hematology

XY0206 targets FLT3-dependent resistance states in acute myeloid leukemia

Abstract

Activating mutations in FMS-like tyrosine kinase 3 (FLT3) drive aggressive acute myeloid leukemia (AML) and confer poor prognosis. Although FLT3 inhibitors have improved AML outcomes, their efficacy is frequently limited by microenvironment-mediated signaling and treatment-emergent resistance. XY0206 is a structurally optimized derivative of sunitinib, an inhibitor approved for multiple solid tumors. Biochemical, multi-omics, and functional analyses showed that XY0206 directly engages FLT3 and suppresses downstream STAT5, AKT, and ERK signaling, resulting in apoptosis of AML cells with FLT3–internal tandem duplications (FLT3-ITD). Across models of FLT3-dependent resistance, XY0206 retained antileukemic activity, including in FLT3-ITD cells harboring the F691L gatekeeper mutation, a recurrent alteration conferring resistance to approved FLT3 inhibitors. In primary AML blasts and xenograft models, XY0206 exhibited enhanced antileukemic activity with favorable tolerability relative to gilteritinib. In a phase I/II trial of XY0206 monotherapy in patients with relapsed or refractory (R/R) AML (ClinicalTrials.gov identifier NCT04471064), XY0206 achieved a composite complete remission rate (CRc) of 45.7% overall, with a notable 60.0% CRc rate among patients with FLT3-ITD mutations. Three of 8 patients with prior FLT3 inhibitor–exposed R/R AML also achieved CRc. Together, these findings support further clinical evaluation of XY0206 as an FLT3-directed therapeutic in AML, particularly in disease settings with reduced sensitivity to existing FLT3 inhibitors.

Authors

Long Shen, Yang Yang, Chenghua Xu, Bo Jiang, Xiaoxiao Duan, Xianfeng Shao, Simeng Li, Siyi Liu, Chao Huang, Lin Song, Mingyuan Sun, Jinting Fan, Ning Wang, Dong Zhang, Youyang Fang, Lichun Kang, Yajun Jiang, Mingming Niu, Junyuan Qi, Tao Cheng, Hong Wang

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Figure 1

Biochemical and multi-omics profiling define an FLT3-centered inhibitory profile of XY0206.

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Biochemical and multi-omics profiling define an FLT3-centered inhibitory...
(A) Chemical structures of sunitinib and XY0206, with structural differences highlighted in blue and red. (B) Kinase inhibition profiling of XY0206 at 100 nM across 217 kinases. (C) Workflow for proteomic and phosphoproteomic profiling of FLT3-ITD AML cells treated with sunitinib or XY0206. (D) Scatterplots of differentially expressed proteins after sunitinib or XY0206 treatment. Red and blue dots indicate upregulated and downregulated proteins, respectively; selected proteins are labeled. (E) Pathway enrichment analysis of proteins regulated by XY0206 or sunitinib. NES, normalized enrichment score. (F) GSEA of phosphosite alterations after XY0206 or sunitinib treatment. Canonical pathways were obtained from MSigDB. (G) Kinase activity inference based on tyrosine-enriched phosphoproteomics using KSEA and RoKAI. Kinases shown were identified by both methods, with P < 0.05 and at least 2 substrate sites. Node shapes indicate treatment specificity: triangles, sunitinib-specific; pentagons, XY0206-specific; circles, shared. (H) Integrated FLT3 pathway map showing MS-derived protein and phosphosite-level changes after treatment. Heatmap values indicate log2 fold changes (FCs) from the corresponding proteomic or phosphoproteomic datasets; they should not be interpreted as phosphorylation (Phospho) occupancy, absolute phosphoprotein abundance, or mathematically combinable values across datasets. (I) Immunoblot analysis of total and phosphorylated FLT3, STAT5, AKT, ERK1/2, and c-MYC in MOLM13 cells treated with XY0206 or sunitinib (10 nM) for 3 hours. Numbers below blots indicate densitometric ratios normalized to total protein or GAPDH and scaled to DMSO. Immunoblots were repeated independently at least twice with similar results.