Discovery of 2-Aminopyrimidine Derivatives as Potent Dual FLT3/CHK1 Inhibitors with Significantly Reduced hERG Inhibitory Activities

Abstract

FLT3 inhibitors as single agents have limited effects because of acquired and adaptive resistance and the cardiotoxicity related to human ether-a-go-go-related gene (hERG) channel blockade further impedes safe drugs to the market. Inhibitors having potential to overcome resistance and reduce hERG affinity are highly demanded. Here, we reported a dual FLT3/CHK1 inhibitor 18, which displayed potencies to overcome varying acquired resistance in BaF3 cells with FLT3-TKD and FLT3-ITD-TKD mutations. Moreover, 18 displayed high selectivity over c-KIT more than 1700-fold and greatly reduced hERG affinity, with an IC50 value of 58.4 μM. Further mechanistic studies demonstrated 18 can upregulate p53 and abolish the outgrowth of adaptive resistant cells. In the in vivo studies, 18 demonstrated favorable PK profiles and good safety, suppressed the tumor growth in the MV-4–11 cell inoculated mouse xenograft model, and prolonged the survival in the Molm-13 transplantation model, supporting its further development.

Structure-Based Optimization of Pyrazinamide-Containing Macrocyclic Derivatives as Fms-like Tyrosine Kinase 3 (FLT3) Inhibitors to Overcome Clinical Mutations

“…However, the GK mutation F691L showed universal resistance to the available second-generation FLT3 inhibitors 4 and 5 due to the loss of interaction or inducing steric hindrance with them. , The macrocyclic inhibitor pacritinib ( 6 ) is currently in clinical phase II for the treatment of AML, but its inhibitory activity against FLT3 F691L is also unsatisfactory (Ba/F3-FLT3-ITD-F691L = 291 nM) . Several FLT3 inhibitors that can effectively overcome D835Y and F691L mutations simultaneously have been reported, such as FF-10101 and TLX83 (Figure S1), − which are still in biological studies or early stages of clinical testing. The secondary mutations, especially F691L, have emerged as the primary resistance mechanism of action of FLT3 inhibitors and served as an unmet clinic need.…”