Allosteric targeting of RIPK1: discovery of novel inhibitors <i>via</i> parallel virtual screening and structure-guided optimization
Receptor-interacting serine/threonine protein-kinase 1 (RIPK1) is a critical signalling protein that regulates inflammation and cell death in response to TNF signalling. Inhibiting RIPK1 kinase activity prevents neuronal cell death in various animal models, making it a promising therapeutic target for neurodegenerative, inflammatory, and autoimmune disorders. To identify novel allosteric RIPK1 inhibitors, we used a parallel virtual screening strategy that employed structure-based pharmacophore, shape-based, and fuzzy pharmacophore similarity approaches. Structure-guided optimization enabled by X-ray crystallography led to the discovery of a potent and selective piperidinecarboxamide inhibitor with an acceptable pharmacokinetic (PK) profile and limited brain exposure. This work highlights the effectiveness of virtual screening, followed by structure-guided optimization, in identifying progressible allosteric kinase inhibitors.
Authors
- Yaíma L. Lightfoot (ORCID: https://orcid.org/0009-0001-2153-1906)
- Christian Rodriguez (ORCID: https://orcid.org/0000-0003-3962-7268)
- Naphtali J. Reyna
- Dana E. Pfaffinger
- Fernando Álvarez (ORCID: https://orcid.org/0000-0002-7347-5483)
- Yongying Jiang (ORCID: https://orcid.org/0000-0001-7774-0136)
- Sven Johannsson
- Jason B. Cross (ORCID: https://orcid.org/0000-0002-0919-2833)
- Hannah Shepard
- Philip H. Jones (ORCID: https://orcid.org/0000-0002-5904-795X)
- Mary Geck (ORCID: https://orcid.org/0009-0000-2927-9402)
- Georg Kempf (ORCID: https://orcid.org/0000-0002-0228-6730)
- K. Maskos
- Matthew M. Hamilton (ORCID: https://orcid.org/0000-0002-1703-1685)
- Jennifer Bardenhagen (ORCID: https://orcid.org/0009-0003-2442-8327)
- Sunil Goodwani
- R. S. K. Vijayan (ORCID: https://orcid.org/0000-0003-4868-8214)
- William J. Ray (ORCID: https://orcid.org/0000-0002-4491-167X)
- Richard T. Lewis
- Lars Neumann
- Quanyun A. Xu
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- ProterixBio (United States) (US)
Publication Details
- Journal
- RSC Medicinal Chemistry
- Published
- 2025-01-01
- DOI
- https://doi.org/10.1039/d5md00317b
- Citations
- 1
- Primary Topic
- Cell death mechanisms and regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.81