Un-LOK-ing a New Approach for Conformational Selective Targeting of STK10 (LOK)
STK10 (serine/threonine kinase 10, LOK), is an important regulator of diverse cellular processes, such as cell cycle progression and lymphocyte migration. STK10 has emerged as a potential therapeutic target for diseases associated with impaired cell migration and cell division. Here, we present a late-stage optimization of a macrocyclic pyrazolo-[1,5-<i>a</i>]-pyrimidine scaffold that led to a urea-based lead series targeting the back-pocket of STK10. Co-crystal structure analysis of <b>23</b> revealed that the optimized macrocycles adopted a unique binding mode that protrudes deep into the back-pocket of STK10. Compound <b>23</b> exhibited potent on-target activity in biophysical and activity assays and displayed nanomolar activity for STK10 in cells. In addition, <b>23</b> shows good selectivity against the kinome and remarkably also against the closely related kinase SLK (STE20-like kinase). Therefore, we propose that targeting the unique and largely extended pocket in STK10 represents an opportunity to develop highly selective STK10 inhibitors.
Authors
- L M Wahl (ORCID: https://orcid.org/0009-0002-1354-1503)
- Christian Georg Kurz (ORCID: https://orcid.org/0000-0001-8584-5827)
- Stefan Knapp (ORCID: https://orcid.org/0000-0001-5995-6494)
- Krishna Saxena (ORCID: https://orcid.org/0000-0002-2237-5378)
- Martina Dettenhöfer (ORCID: https://orcid.org/0009-0001-2150-2435)
- Christopher Lenz (ORCID: https://orcid.org/0009-0000-2261-2823)
- Benedict‐Tilman Berger (ORCID: https://orcid.org/0000-0002-3314-2617)
- Martin Schröder (ORCID: https://orcid.org/0000-0001-7631-7766)
- Martin P. Schwalm (ORCID: https://orcid.org/0000-0002-1252-1829)
- Susanne Müller (ORCID: https://orcid.org/0000-0003-2402-4157)
- Lewis Elson (ORCID: https://orcid.org/0009-0004-6142-3653)
- Jennifer Alisa Amrhein (ORCID: https://orcid.org/0000-0003-3416-644X)
- Thomas Hanke (ORCID: https://orcid.org/0000-0001-7202-9468)
- Andreas Krämer (ORCID: https://orcid.org/0000-0003-3294-2660)
- Joshua Gerninghaus
- Francesco Greco (ORCID: https://orcid.org/0000-0002-4079-6977)
- Theresa Elisabeth Mensing
- Laura Nadine Tandara
Institutions
- Goethe University Frankfurt (DE)
- German Cancer Research Center (DE)
- Frankfurt Institute for Advanced Studies (DE)
- German Cancer Society (DE)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2025-10-14
- DOI
- https://doi.org/10.1021/acsmedchemlett.5c00479
- Citations
- 1
- Primary Topic
- NF-κB Signaling Pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.94