6H-Indolo-[2,3-b]-quinoxaline derivatives as promising bifunctional SHP1 inhibitors†

Dysfunction in the SHP1 enzyme can cause cancers and many diseases, so it is of great significance to develop novel small molecule SHP1 inhibitors. Through continuous monitoring of metabolic and targeted processes of SHP1 inhibitors in real-time, we can evaluate the effectiveness and toxicity of the inhibitors, further optimize drug design, and explore SHP1 biology. Indoloquinoxaline is an important class of N-containing heterocycle, which has been studied and applied in the pharmacological field and in optoelectronic materials. In this work, the potential Src homology 2 domain-containing phosphatase 1 (SHP1) inhibitor 5a was developed with the help of the structural fusion and scaffold hop of a fluorophore, 6H-indolo-[2,3-b]-quinoxaline, and a bio-active skeleton, thieno[2,3-b]quinoline-procaine. Compound 5a selectively inhibited the SHP1^PTP enzyme abilities (IC₅₀ = 2.34 ± 0.06 μM), exhibited a significant fluorescence response (P = 0.007) in response to SHP1^PTP activity, and emitted strong blue/green fluorescence in MDA-MB-231 cells. Furthermore, compound 5a showed irreversible binding with SHP1^PTP in simulations and dialysis experiments. Altogether, compound 5a serves as a bifunctional SHP1 inhibitor, combining imaging and therapeutic functionalities, enhancing our understanding of SHP1 biological mechanisms, and positively impacting novel drug development.