Un-LOK-ing a New Approach for Conformational Selective Targeting of STK10 (LOK)

Martina Dettenhöfer; Laura Nadine Tandara; Jennifer Alisa Amrhein; Christian Georg Kurz; Martin Peter Schwalm; Theresa Elisabeth Mensing; Laurenz Maximilian Wahl; Andreas Krämer; Joshua Gerninghaus; Christopher Lenz; Lewis Elson; Benedict-Tilman Berger; Martin Schröder; Krishna Saxena; Susanne Müller; Stefan Knapp; Francesco Aleksy Greco; Thomas Hanke

doi:10.1021/acsmedchemlett.5c00479

Un-LOK-ing a New Approach for Conformational Selective Targeting of STK10 (LOK)

ACS Med Chem Lett. 2025 Oct 14;16(11):2086-2096. doi: 10.1021/acsmedchemlett.5c00479. eCollection 2025 Nov 13.

Authors

Martina Dettenhöfer^{1

2}, Laura Nadine Tandara^{1

2}, Jennifer Alisa Amrhein^{1

2}, Christian Georg Kurz^{1

2}, Martin Peter Schwalm^{1

2

3}, Theresa Elisabeth Mensing^{1

2}, Laurenz Maximilian Wahl^{1

2}, Andreas Krämer^{1

2

3}, Joshua Gerninghaus^{1

2}, Christopher Lenz^{1

2}, Lewis Elson^{1

2}, Benedict-Tilman Berger^{1

2}, Martin Schröder^{1

2}, Krishna Saxena^{1

2}, Susanne Müller^{1

2}, Stefan Knapp^{1

2

3}, Francesco Aleksy Greco^{1

2

3}, Thomas Hanke^{1

2}

Affiliations

¹ Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany.
² Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Strasse 15, 60438 Frankfurt am Main, Germany.
³ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), DKTK Site Frankfurt-Mainz, 69120 Heidelberg, Germany.

PMID: 41256983
PMCID: PMC12621043 (available on 2026-11-13)
DOI: 10.1021/acsmedchemlett.5c00479

Abstract

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-a]-pyrimidine scaffold that led to a urea-based lead series targeting the back-pocket of STK10. Co-crystal structure analysis of 23 revealed that the optimized macrocycles adopted a unique binding mode that protrudes deep into the back-pocket of STK10. Compound 23 exhibited potent on-target activity in biophysical and activity assays and displayed nanomolar activity for STK10 in cells. In addition, 23 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.

Keywords: conformational change; inhibitor binding mode; kinase inhibitor selectivity; macrocyclic inhibitor; rational inhibitor design; serine/threonine kinase 10.