Discovery of Anti-apoptotic BAX Inhibitors
Abstract BAX is a critical regulator of the apoptosis cascade and its abnormal activation contributes to the development of disease including cardiovascular and neurodegenerative disorders. Therefore, BAX represents an attractive target for the pharmacological inhibition of pathological cell death. Based on a virtual screen, we identified and modified several EGFR kinase inhibitors with potential activity against BAX. Systematic modifications of the dacomitinib and gefitinib core structure were performed, allowing us to elucidate how structural modifications influence biological activity and leading to a comprehensive structure-activity relationship (SAR) on BAX inhibition. The developed series has favorable drug-like properties and improved BAX inhibitory activity in vitro, in cells, and in human induced pluripotent stem cell-derived brain organoids, with significantly reduced EGFR kinase activity. This series therefore represents a promising starting point for the development of improved and potentially therapeutic BAX inhibitors.
Authors
- Edgar Specker (ORCID: https://orcid.org/0000-0002-9471-9520)
- Justin Kale (ORCID: https://orcid.org/0000-0002-4915-0806)
- Lina Hellwig (ORCID: https://orcid.org/0000-0003-4430-8384)
- Silke Radetzki (ORCID: https://orcid.org/0000-0003-2688-2868)
- Keven Mallow
- Rima Al‐awar (ORCID: https://orcid.org/0000-0002-4185-055X)
- David Uehling (ORCID: https://orcid.org/0000-0002-9748-0500)
- Arundhasa Chandrabalan (ORCID: https://orcid.org/0009-0001-6490-1719)
- Jörg Contzen
- Marc Nazaré (ORCID: https://orcid.org/0000-0002-1602-2330)
- Max Ruwolt (ORCID: https://orcid.org/0009-0000-7220-406X)
- Scott Houliston (ORCID: https://orcid.org/0000-0002-0113-0339)
- Andreas Oder (ORCID: https://orcid.org/0009-0004-9852-3818)
- David William Andrews (ORCID: https://orcid.org/0000-0002-9266-7157)
- Philipp Mergenthaler (ORCID: https://orcid.org/0000-0002-9753-6711)
- Jens Peter von Kries (ORCID: https://orcid.org/0000-0003-4716-4988)
- Han Sun (ORCID: https://orcid.org/0000-0002-1655-0838)
- Justin P. Pogmore (ORCID: https://orcid.org/0000-0003-4198-2779)
- Martin Neuenschwander (ORCID: https://orcid.org/0000-0002-3114-7975)
- Marta Diceglie (ORCID: https://orcid.org/0009-0002-2668-3631)
- Fan Liu (ORCID: https://orcid.org/0000-0002-2358-549X)
- Tao Xin
- Anton F. Ketzel (ORCID: https://orcid.org/0009-0001-1741-0650)
- Annette Aigner
Institutions
- Ontario Institute for Cancer Research (CA)
- Sunnybrook Health Science Centre (CA)
- University Health Network (CA)
- University of Toronto (CA)
- Bielefeld University (DE)
- University of Oxford (GB)
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (DE)
- Sunnybrook Hospital (CA)
- Technische Universität Berlin (DE)
- Freie Universität Berlin (DE)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-10-14
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c01594
- Primary Topic
- Cell death mechanisms and regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Volkswagen Foundation
- Else Kröner-Fresenius-Stiftung
- Einstein Stiftung Berlin
- Stiftung Charité
- Canadian Institutes of Health Research
- H2020 Health