Synthesis and anti‐tumor activity evaluation of 1H‐pyrrolo[2,3‐b]pyridine‐2‐carboxamide derivatives with phenyl sulfonamide groups as potent RSK2 inhibitors

Abstract

AbstractRibosome S6 Protein Kinase 2 (RSK2) is involved in many signal pathways such as cell growth, proliferation, survival and migration in tumors. Also, RSK2 can phosphorylate YB‐1, which induces the expression of tumor initiating cells, leading to poor prognosis of triple negative breast cancer. Herein, phenyl sulfonamide was introduced to a series of 1H‐pyrrolo[2,3‐b]pyridine‐2‐carboxamide derivatives to obtain novel RSK2 inhibitors which were evaluated RSK2 inhibitory activity and proliferation inhibitory activity against MDA‐MB‐468. The newly introduced sulfonamide group was observed to form a hydrogen bond with target residue LEU‐74 which played crucial role in activity. The results showed that most of compounds exhibited RSK2 enzyme inhibitory with IC50 up to 1.7 nM. Compound B1 exhibited the strongest MDA‐MB‐468 cell anti‐proliferation activity (IC50 = 0.13 μM). The in vivo tumor growth inhibitory activities were evaluated with compounds B1‐B3 in MDA‐MB‐468 xenograft model which gave up to 54.6% of TGI.