The polypharmacy combination of the BCL-2 inhibitor venetoclax (VEN) and the FLT3 inhibitor gilteritinib (GIL) is more active in acute myeloid leukemia cells than novel polypharmacologic BCL-2/FLT3 VEN–GIL hybrid single-molecule inhibitors.

Current treatments for acute myeloid leukemias (AMLs) cure fewer than 30% of patients. This low efficacy is due, in part, to the inter-patient and intra-patient heterogeneity of AMLs; accordingly, all current AML treatment regimens involve drug combinations (polypharmacy). A recently-completed clinical trial in relapsed/refractory AML using a combination of two newer targeted antileukemics, the BCL-2 inhibitor venetoclax (VEN) plus the FLT3 inhibitor gilteritinib (GIL), yielded highly promising results for this two-drug polypharmacy combination. Polypharmacology – wherein a single drug molecule that inhibits two or more biological targets is created – has been proposed to offer superior therapeutic results, as compared to the corresponding polypharmacy approach. Herein, we designed and synthesized several polypharmacologic dual BCL-2/FLT3 hybrid single-molecule inhibitors by tethering VEN to GIL, through their solvent-exposed domains. While the in vitro antileukemic activity of the two-drug VEN + GIL polypharmacy combination proved superior to our focused library of VEN-GIL hybrids, alternative grafting points on GIL may yield improved results for future hybrid compounds.