Identification of a highly efficient dual type I/II FMS-like tyrosine kinase inhibitor that disrupts the growth of leukemic cells. Issue 3 (17th March 2022)

• Record Type: Journal Article
• Authors: Beyer, Mandy; Henninger, Sven J.; Haehnel, Patricia S.; Mustafa, Al-Hassan M.; Gurdal, Ece; Schubert, Bastian; Christmann, Markus; Sellmer, Andreas; Mahboobi, Siavosh; Drube, Sebastian; Sippl, Wolfgang; Kindler, Thomas; Krämer, Oliver H.
• Is Part Of: Cell chemical biology. Volume 29:Issue 3(2022)
• Page Start: 398
• Page End: 411.e4
• Publication Date: 2022-03-17
• Subjects: Acute myeloid leukemia -- FMS-like tyrosine kinase-3 -- next generation tyrosine kinase inhibitor -- therapy resistance -- tyrosine kinase domain -- TKi -- p27 -- molecular modeling -- FLT3-ITD -- FLT3-TKD; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2021.10.011
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: Internal tandem duplications (ITDs) in the FMS-like tyrosine kinase-3 (FLT3) are causally linked to acute myeloid leukemia (AML) with poor prognosis. Available FLT3 inhibitors (FLT3i) preferentially target inactive or active conformations of FLT3. Moreover, they co-target kinases for normal hematopoiesis, are vulnerable to therapy-associated tyrosine kinase domain (TKD) FLT3 mutants, or lack low nanomolar activity. We show that the tyrosine kinase inhibitor marbotinib suppresses the phosphorylation of FLT3-ITD and the growth of permanent and primary AML cells with FLT3-ITD. This also applies to leukemic cells carrying FLT3-ITD/TKD mutants that confer resistance to clinically used FLT3i. Marbotinib shows high selectivity for FLT3 and alters signaling, reminiscent of genetic elimination of FLT3-ITD. Molecular docking shows that marbotinib fits in opposite orientations into inactive and active conformations of FLT3. The water-soluble marbotinib-carbamate significantly prolongs survival of mice with FLT3-driven leukemia. Marbotinib is a nanomolar next-generation FLT3i that represents a hybrid inhibitory principle. Graphical abstract: Highlights: Marbotinib is a nanomolar and specific next-generation FLT3i Marbotinib inhibits FLT3-ITD and FLT3-ITD/TKD mutations as a double-edged sword TKi Marbotinib inhibits the growth of permanent and primary AML cells Water-soluble marbotinib-carbamate prolongs survival of mice with FLT3-driven leukemia Abstract : Beyer et al., characterize the highly selective and specific FLT3 inhibitor marbotinib and its water-soluble derivate. These agents suppress the phosphorylation of hyperactive FLT3 and the growth of permanent and primary AML cells with FLT3-ITD and FLT3-ITD/TKD mutants. Marbotinib binds inactive and active conformations of FLT3 in opposite orientations.