IRAK1/4/pan-FLT3 Kinase Inhibitors with Reduced hERG Block as Treatments for Acute Myeloid Leukemia

  • ACS Med Chem Lett. 2025 Apr 29;16(5):887-895. doi: 10.1021/acsmedchemlett.5c00147.
Scott B Hoyt  1 ,  Chris J Finocchio  1 ,  Elizabeth Croll  1 ,  Gregory J Tawa  1 ,  Mingliang Zhang  2 ,  Jiangong Wang  2 ,  Huixi Li  2 ,  Li Ma  2 ,  Kaikai Li  2 ,  Xiaohu Zhang  1 ,  Xin Xu  1 ,  Pranav Shah  1 ,  Yuhong Fang  1 ,  Lyndsey C Bolanos  3 ,  Gabriel Gracia-Maldonado  4 ,  Amal Kolt  4 ,  Christina Robinson  5 ,  Jessica Free  5 ,  Elijah F Edmondson  5 ,  Simone Difilippantonio  5 ,  LaQuita M Jones  6 ,  Ashley E Culver-Cochran  3 ,  Jan S Rosenbaum  4 ,  Daniel T Starczynowski  3 ,  Craig J Thomas  1  7
Affiliations
  • 1. National Center for Advancing Translational Sciences, Rockville, Maryland 20850, United States.
  • 2. WuXi AppTec Co. Ltd., 168 Nanhai Road, TEDA, Tianjin 300457, People's Republic of China.
  • 3. Cincinnati Children's Hospital Medical Center, Division of Experimental Hematology, Cincinnati, Ohio 45229, United States.
  • 4. Kurome Therapeutics, Cincinnati, Ohio 45208, United States.
  • 5. Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, United States.
  • 6. Cincinnati Children's Hospital Medical Center, Division of Oncology, Cincinnati, Ohio 45229, United States.
  • 7. National Cancer Institute, Bethesda, Maryland 20814, United States.
PMID: 40365393 DOI: 10.1021/acsmedchemlett.5c00147
Abstract

We report the optimization of a series of IRAK1/4/pan-FLT3 kinase inhibitors. These efforts have produced a key compound 27 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), 27 produces survival prolongation superior to that of gilteritinib, the leading FDA-approved FLT3 Inhibitor currently used to treat AML.

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