A novel, dual pan-PIM/FLT3 inhibitor SEL24 exhibits broad therapeutic potential in acute myeloid leukemia

Abstract

Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is one of the most common genetic lesions in acute myeloid leukemia patients (AML). Although FLT3 tyrosine kinase inhibitors initially exhibit clinical activity, resistance to treatment inevitably occurs within months. PIM kinases are thought to be major drivers of the resistance phenotype and their inhibition in relapsed samples restores cell sensitivity to FLT3 inhibitors. Thus, simultaneous PIM and FLT3 inhibition represents a promising strategy in AML therapy. For such reasons, we have developed SEL24-B489 - a potent, dual PIM and FLT3-ITD inhibitor. SEL24-B489 exhibited significantly broader on-target activity in AML cell lines and primary AML blasts than selective FLT3-ITD or PIM inhibitors. SEL24-B489 also demonstrated marked activity in cells bearing FLT3 tyrosine kinase domain (TKD) mutations that lead to FLT3 inhibitor resistance. Moreover, SEL24-B489 inhibited the growth of a broad panel of AML cell lines in xenograft models with a clear pharmacodynamic-pharmacokinetic relationship. Taken together, our data highlight the unique dual activity of the SEL24-B489 that abrogates the activity of signaling circuits involved in proliferation, inhibition of apoptosis and protein translation/metabolism. These results underscore the therapeutic potential of the dual PIM/FLT3-ITD inhibitor for the treatment of AML.

Mechanisms Underlying Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia

“…In addition, several agents that may overcome or prevent resistance are currently under investigation. A pan-PIM/FLT3 inhibitor SEL24 [ 112 ], a type II FLT3 inhibitor MZH29 [ 113 ], a MERTK/FLT3 inhibitor MRX-2843 [ 114 ], a BCR-ABL inhibitor ponatinib [ 115 ], and a multiple tyrosine kinase inhibitor cabozantinib [ 116 ] have exhibited anti-tumor activity in cases with FLT3-TKD, including those with the F691 pointmutation.…”

Current perspectives on targeting PIM kinases to overcome mechanisms of drug resistance and immune evasion in cancer

“…Testing of a first-in-class dual PIM and FLT3-ITD inhibitor, SEL24-B489 is underway for AML patients (Czardybon et al, 2018). Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is a common genetic lesion in AML patients with 70% of newly diagnosed patients exhibiting its expression with a further 30% showing activating mutations of the receptor J o u r n a l P r e -p r o o f Journal Pre-proof (Thiede et al, 2002).…”

FLT3 inhibitors in acute myeloid leukemia

“…SEL24-B489 suppresses the growth of AML cell lines. Unlike selective FLT3/ITD or PIM inhibitors, SEL24-B489 exhibits significantly broader on-target activity in AML cell lines, primary AML blasts, and FLT3-TKD-mutated cells [ 76 ].…”