Rational Design, Synthesis and Biological Evaluation of Pyrimidine-4,6-diamine derivatives as Type-II inhibitors of FLT3 Selective Against c-KIT

Nicholas Mcconnell,Brendan Frett,Gunaganti Naresh,Lucky Ding,Hong-Yu Li,Neil P Shah,Jaideep B Bharate,Lingtian Zhang,Naga Rajiv Lakkaniga

doi:10.1038/s41598-018-21839-3

Abstract

FMS-like Tyrosine Kinase 3 (FLT3) is a clinically validated target for acute myeloid leukemia (AML). Inhibitors targeting FLT3 have been evaluated in clinical studies and have exhibited potential to treat FLT3-driven AML. A frequent, clinical limitation is FLT3 selectivity, as concomitant inhibition of FLT3 and c-KIT is thought to cause dose-limiting myelosuppression. Through a rational design approach, novel FLT3 inhibitors were synthesized employing a pyridine/pyrimidine warhead. The most potent compound identified from the studies is compound 13a, which exhibited an IC50 value of 13.9 ± 6.5 nM against the FLT3 kinase with high selectivity over c-KIT. Mechanism of action studies suggested that 13a is a Type-II kinase inhibitor, which was also supported through computer aided drug discovery (CADD) efforts. Cell-based assays identified that 13a was potent on a variety of FLT3-driven cell lines with clinical relevance. We report herein the discovery and therapeutic evaluation of 4,6-diamino pyrimidine-based Type-II FLT3 inhibitors, which can serve as a FLT3-selective scaffold for further clinical development.

Highlights

Through computer aided drug discovery (CADD) followed by in-vitro validation, our group has discovered an imidazopyridine core as a unique heterocycle inhibiting the FMS-like Tyrosine Kinase 3 (FLT3) kinase[24]
A series of extended compounds comprising pyrimidine as the kinase-hinge warhead connected to two aromatic rings (A and B) via an amine bond were synthesized
The FLT3 inhibition results presented in Tables 1–4 are indicative of the fact that there are several key structure-activity relationship features

Summary

Introduction

Through computer aided drug discovery (CADD) followed by in-vitro validation, our group has discovered an imidazopyridine core (example 4) as a unique heterocycle inhibiting the FLT3 kinase[24]. The imidazopyridine 4 showed FLT3 inhibition with an IC50 value of 16 nM Other heterocycles, such as those containing pyrimidine, have been reported as FLT3 kinase inhibitors. We designed a series of longer compounds comprising pyrimidine as the kinase-hinge warhead (central heterocycle shown in Fig. 2) connected to two aromatic rings (A and B) via an amine bond. We hypothesized these compounds to be potent inhibitors of the FLT3 kinase through CADD studies. We discuss the discovery and therapeutic evaluation of 4,6-diamino pyrimidines as selective, FLT3 inhibitors

Methods

Results

Conclusion