# A Selective MAP3K1 Inhibitor Facilitates Discovery of NPM1 as a Member of the Network

## TL;DR

Researchers developed a new quinoxaline-based drug that selectively inhibits MAP3K1 and discovered NPM1 as part of its network.

## Contribution

A selective MAP3K1 inhibitor with improved properties was synthesized and used to identify NPM1 in the MAP3K1 network.

## Key findings

- Compound 51-106 is a selective and orally bioavailable MAP3K1 inhibitor.
- Proteomics studies revealed NPM1 as a novel member of the MAP3K1 network.
- The inhibitor shows improved metabolic stability compared to previous analogs.

## Abstract

The quinoxaline core is found in several biologically active compounds, with Erdafitinib being the first FDA-approved quinoxaline derivative that targets a kinase and exhibits anti-cancer properties. We previously reported a quinoxaline analog (84) that displayed anti-cancer effects by inhibiting IKKβ, a key kinase in the NFκB pathway. Here, we present the synthesis of a regioisomer (51-106) and its characterization as a selective MAP3K1 inhibitor with improved metabolic stability and oral bioavailability. We used the small molecule MAP3K1 inhibitor in a proteomics study that identified NPM1 as a member of the MAP3K1 network.