Riding toward Selectivity: Optimization of Covalent 7-Azaindole-Based BMX Kinase Inhibitors PMID: 42441922

ADC Targets in Oncology

2026-04-10

Riding toward Selectivity: Optimization of Covalent 7-Azaindole-Based BMX Kinase Inhibitors

J Med Chem. 2026 Jul 23;69(14):17416-17447. doi: 10.1021/acs.jmedchem.6c01366.

Xiaojun Julia Liang ¹ ² ³ , Claudia Albertini ³ ⁴ , Thales Kronenberger ³ ⁵ ⁶ ⁷ , Ekaterina Shevchenko ³ ⁵ ⁶ , Alexander Rasch ³ , Benedict-Tilman Berger ⁸ ⁹ , Martin Schwalm ⁸ ⁹ ¹⁰ , Lena Marie Berger ⁸ ⁹ , Andreas Krämer ⁸ ⁹ ¹⁰ , Ricardo A M Serafim ¹ ³ ¹¹ , Michael Forster ² ³ , Apirat Chaikuad ⁸ ⁹ , Maria Laura Bolognesi ⁴ , Susanne Müller ⁸ ⁹ ¹⁰ , Antti Poso ² ³ ⁵ ⁶ , Stefan Laufer ² ³ ⁵ , Stefan Knapp ⁸ ⁹ ¹⁰ , Matthias Gehringer ¹ ² ³

Affiliations

1. Department for Medicinal Chemistry, Institute for Biomedical Engineering, Faculty of Medicine, University of Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
2. Cluster of Excellence iFIT (EXC 2180) 'Image-Guided & Functionally Instructed Tumor Therapies', University of Tübingen, 72076 Tübingen, Germany.
3. Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmaceutical Sciences, Faculty of Sciences, University of Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
4. Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
5. Tübingen Center for Academic Drug Discovery & Development (TüCAD2), 72076 Tübingen, Germany.
6. School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
7. Institute of Medical Microbiology and Hygiene, Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Elfriede-Aulhorn-Str. 6, 72076 Tübingen, Germany.
8. Structural Genomics Consortium, Goethe University Frankfurt, Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, Germany.
9. Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Straße 9, 60438 Frankfurt am Main, Germany.
10. Frankfurt Cancer Institute (FCI) and German Translational Cancer Network (DKTK) Site Frankfurt/Mainz, 60438 Frankfurt am Main, Germany.
11. Department of Organic and Pharmaceutical Chemistry, School of Engineering, Institut Químic de Sarrià (IQS), Universitat Ramon Llull (URL), Vía Augusta 390, 08017 Barcelona, Spain.

Abstract

The tyrosine kinase expressed in hepatocellular carcinoma (TEC) family comprises five nonreceptor tyrosine kinases─BTK, Itk, BMX, TXK, and TEC─with key roles in immune signaling. Although Btk and Itk have been extensively studied, selective inhibitors for TEC, TXK, and BMX remain scarce. Recently, we identified 7-azaindole-based covalent BMX inhibitors with potent inhibitory activity and robust cellular target engagement but limited selectivity across TEC family members, especially Btk. Here, we describe a new generation of BMX inhibitors designed to exploit subtle structural differences between BMX and Btk by incorporating diverse N-acylamino substituents at the azaindole 5-position or variations at the linker and warhead. Our compounds display subnanomolar BMX potency and improved selectivity over Btk and Other TEC kinases. Key compound 11i showed strong cellular target engagement, good in vitro metabolic stability, a favorable kinome profile, and rapid covalent inactivation kinetics, positioning it among the best BMX chemical probes currently available.