2. Academic Validation
  3. IRAK1/4/pan-FLT3 Kinase Inhibitors with Reduced hERG Block as Treatments for Acute Myeloid Leukemia

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

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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