Discovery of IRAK1/4/pan-FLT3 Kinase Inhibitors as Treatments for Acute Myeloid Leukemia

Scott B Hoyt ¹, Chris J Finocchio ¹, Elizabeth Croll ¹, Gregory J Tawa ¹, Huixu Li ², Li Ma ², Kaikai Li ², Li Liu ², Ranran Li ², Xiaohu Zhang ¹, Kelli Wilson ¹, Xin Xu ¹, Pranav Shah ¹, Jordan Williams 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}
 
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.

ABSTRACT

We report the discovery of an imidazopyridine series of IRAK1/4/pan-FLT3 kinase inhibitors. Optimization of this series has produced compound 31 which displays potent and selective inhibition of IRAK1, IRAK4, FLT3, and all mutant forms of FLT3, as well as good in vitro ADME and pharmacokinetic properties. In a mouse xenograft model of AML, 31 produces survival prolongation equal to that of Gilteritinib, the leading marketed FLT3 inhibitor currently used to treat AML.