IRAK1/4/pan-FLT3 Kinase Inhibitors with Reduced hERG Block as Treatments for Acute Myeloid Leukemia
We report the optimization of a series of IRAK1/4/pan-FLT3 kinase inhibitors. These efforts have produced a key compound <b>27</b> that displays potent and selective inhibition of IRAK1, IRAK4, and FLT3, reduced block of hERG, and good pharmacokinetic properties. In a mouse xenograft model of acute myeloid leukemia (AML), <b>27</b> produces survival prolongation superior to that of gilteritinib, the leading FDA-approved FLT3 inhibitor currently used to treat AML.
Authors
- Gabriel Gracia-Maldonado
- Craig J. Thomas (ORCID: https://orcid.org/0000-0001-9386-9001)
- Amal Kolt
- Xiaohu Zhang (ORCID: https://orcid.org/0000-0002-5872-4656)
- Huixi Li (ORCID: https://orcid.org/0000-0001-8666-5780)
- Li Ma (ORCID: https://orcid.org/0000-0003-0685-7745)
- Lyndsey Bolanos (ORCID: https://orcid.org/0000-0002-5447-5277)
- Daniel T. Starczynowski (ORCID: https://orcid.org/0000-0002-5771-7462)
- Simone Difilippantonio
- Ashley E. Culver‐Cochran (ORCID: https://orcid.org/0000-0002-2744-1864)
- Yuhong Fang (ORCID: https://orcid.org/0000-0001-6742-5677)
- Elijah F. Edmondson (ORCID: https://orcid.org/0000-0002-6106-3705)
- Gregory J. Tawa (ORCID: https://orcid.org/0000-0002-5573-308X)
- Jan S. Rosenbaum (ORCID: https://orcid.org/0000-0002-8509-5939)
- Christina M. Robinson (ORCID: https://orcid.org/0000-0001-5336-9459)
- LaQuita M. Jones (ORCID: https://orcid.org/0000-0001-9877-9558)
- Jiangong Wang (ORCID: https://orcid.org/0000-0002-0259-0118)
- Mingliang Zhang (ORCID: https://orcid.org/0000-0003-2285-3592)
- Kaikai Li (ORCID: https://orcid.org/0000-0003-1505-9438)
- Xin Xu (ORCID: https://orcid.org/0000-0003-1163-9304)
- Pranav Shah (ORCID: https://orcid.org/0000-0003-0076-7159)
- Scott B. Hoyt (ORCID: https://orcid.org/0009-0009-9788-1935)
- Chris J. Finocchio
- Jessica Free
- Elizabeth Croll
Institutions
- Cincinnati Children's Hospital Medical Center (US)
- WuXi AppTec (China) (CN)
- Frederick National Laboratory for Cancer Research (US)
- International Society for Experimental Hematology (US)
- National Center for Advancing Translational Sciences (US)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2025-04-29
- DOI
- https://doi.org/10.1021/acsmedchemlett.5c00147
- Citations
- 4
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 7.08
Funders
- National Institutes of Health
- National Cancer Institute
- National Center for Advancing Translational Sciences