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. 2024 Oct 23;15(11):1843-1851.
doi: 10.1021/acsmedchemlett.4c00269. eCollection 2024 Nov 14.

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
Affiliations

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

Scott B Hoyt et al. ACS Med Chem Lett. .

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.

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Conflict of interest statement

The authors declare the following competing financial interest(s): D.T.S. serves on the scientific advisory board at Kurome Therapeutics; is a consultant for and/or received funding from Kurome Therapeutics, Captor Therapeutics, Treeline Biosciences, and Tolero Therapeutics; and has equity in Kurome Therapeutics. L.C.B. consulted for Kurome Therapeutics. J.R. is employed by, and holds equity in, Kurome Therapeutics; holds equity in Airway Therapeutics; and is a consultant for Radius Health and MoglingBio. G.G.-M. was employed by, and holds equity in, Kurome Therapeutics. A.K. is employed by, and holds equity in, Kurome Therapeutics. S.B.H. and C.J.T. are inventors on patent WO 2022026935. Their rights have been assigned to the U.S. government, but they may receive royalties on the patent. The remaining authors declare no competing financial interests.

Figures

Figure 1
Figure 1
IRAK-FLT3 inhibitor NCGC-1481 (1).
Figure 2
Figure 2
X-ray cocrystal structure of compound 1 bound to IRAK4.
Figure 3
Figure 3
Kinase selectivity profiles of key compounds. For each off-target kinase, selectivity was calculated vs IRAK4 and represented as fold selectivity (IC50 of off-target kinase/IC50 IRAK4). Based on fold selectivity, each off-target kinase was placed in one of four bins (<10-fold, 10–100 fold, >100–1000 fold, >1000 fold). Percentages refer to percent of 369 kinase panel.
Figure 4
Figure 4
Kaplan–Meier survival analysis of NSGS mice engrafted with MOLM14 (ITD, D835Y) cells and dosed with 10 mg/kg IP compound 31 or Gilteritinib.
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