Small-Molecule Modulators of HIPK4 Activity and Proteostasis.
6 affiliations
- 1Department of Chemical and Systems Biology, Stanford University, Stanford, California94305, United States.
- 2Department of Chemistry, Stanford University, Stanford, California94305, United States.
- 3Sanford Burnham Prebys Medical Discovery Institute , La Jolla, California92037, United States.
- 4Institute of Pharmaceutical Chemistry, Goethe University, 60438Frankfurt Am Main, Germany.
- 5Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, 60438Frankfurt Am Main, Germany.
- 6Department of Developmental Biology, Stanford University, Stanford, California94305, United States.
Abstract
Homeodomain-interacting protein kinase 4 (HIPK4) is a dual-specificity kinase that is predominantly expressed in differentiating spermatids, required for sperm development, and a promising target for nonhormonal male contraception. Genetic and functional studies have established an essential role for HIPK4 in spermiogenesis, where it acts at least in part through regulation of the F-actin-scaffolded acroplaxome during spermatid head shaping. The direct molecular targets of HIPK4 and their downstream effectors remain poorly defined, and small-molecule probes would be versatile tools for further investigating HIPK4 functions. Synthetic HIPK4 ligands could also be valuable leads for the development of nonhormonal male contraceptives. Here, we report the discovery of a cyanoquinoline-based series of HIPK4 inhibitors with nanomolar potency. Our lead compounds are selective for HIPK4, both within the HIPK family and across the broader kinome, establishing this scaffold as a useful starting point for probe and lead development. Unexpectedly, we found that a subset of these cyanoquinolines also perturbs HIPK4 proteostasis in a cell-type-specific manner. In spermatids, these compounds induce the formation of detergent-insoluble HIPK4 aggregates and promote interactions between this kinase and the autophagy receptor Tax1-binding protein 1 (TAX1BP1), potentially reinforcing a native mechanism of HIPK4 regulation. Together, our findings establish cyanoquinoline ligands as a new chemotype for probing HIPK4 biology and advancing male contraceptive discovery.
Related
- Preliminary Evaluation of the Anticancer Activity of a PGK1 Small Molecule Inhibitor in Ishikawa Endometrial Cancer
- Small Molecule Therapeutic Approaches With a Greater Focus on Hearing Loss: A Review
- Small-molecule ACOD1 inhibition attenuates colitis and tumor growth through a shared myeloid mechanism, diverging from genetic deletion
- Small-molecule inhibitors and checkpoint inhibitors in KRAS G12C NSCLC: balancing efficacy and toxicity.
- Efficacy, mechanisms, and influence factors of small molecule targeted therapy in treating rheumatoid arthritis: a multi-dimensional clinical, immunological, and ultrasonographic study
BibTeX
@article{zhuang2026smallmolecule,
title = {{Small-Molecule Modulators of HIPK4 Activity and Proteostasis.}},
author = {Zaile Zhuang and Riley K Togashi and Patrick C Kearney and Ian Pass and Steven M Swick and Fu-Yue Zeng and Andrey A Bobkov and Lynn M Fujimoto and Shubhankar Dutta and Athina Zerva and Nicolai D Raig and Debasmita Saha and Atoosa Emami and Martin P Schwalm and Bradley K Moon and Samuel T Howard and Stefan Knapp and Thomas Hanke and Thomas D Y Chung and James K Chen},
journal = {Journal of the American Chemical Society},
year = {2026},
month = oct,
doi = {10.1021/jacs.6c10097},
url = {https://europepmc.org/article/MED/42837211},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Small-Molecule Modulators of HIPK4 Activity and Proteostasis.
AU - Zaile Zhuang
AU - Riley K Togashi
AU - Patrick C Kearney
AU - Ian Pass
AU - Steven M Swick
AU - Fu-Yue Zeng
AU - Andrey A Bobkov
AU - Lynn M Fujimoto
AU - Shubhankar Dutta
AU - Athina Zerva
AU - Nicolai D Raig
AU - Debasmita Saha
AU - Atoosa Emami
AU - Martin P Schwalm
AU - Bradley K Moon
AU - Samuel T Howard
AU - Stefan Knapp
AU - Thomas Hanke
AU - Thomas D Y Chung
AU - James K Chen
PY - 2026
DA - 2026/10/01
JO - Journal of the American Chemical Society
DO - 10.1021/jacs.6c10097
UR - https://europepmc.org/article/MED/42837211
AB - Homeodomain-interacting protein kinase 4 (HIPK4) is a dual-specificity kinase that is predominantly expressed in differentiating spermatids, required for sperm development, and a promising target for nonhormonal male contraception. Genetic and functional studies have established an essential role for HIPK4 in spermiogenesis, where it acts at least in part through regulation of the F-actin-scaffolded acroplaxome during spermatid head shaping. The direct molecular targets of HIPK4 and their downstream effectors remain poorly defined, and small-molecule probes would be versatile tools for further investigating HIPK4 functions. Synthetic HIPK4 ligands could also be valuable leads for the development of nonhormonal male contraceptives. Here, we report the discovery of a cyanoquinoline-based series of HIPK4 inhibitors with nanomolar potency. Our lead compounds are selective for HIPK4, both within the HIPK family and across the broader kinome, establishing this scaffold as a useful starting point for probe and lead development. Unexpectedly, we found that a subset of these cyanoquinolines also perturbs HIPK4 proteostasis in a cell-type-specific manner. In spermatids, these compounds induce the formation of detergent-insoluble HIPK4 aggregates and promote interactions between this kinase and the autophagy receptor Tax1-binding protein 1 (TAX1BP1), potentially reinforcing a native mechanism of HIPK4 regulation. Together, our findings establish cyanoquinoline ligands as a new chemotype for probing HIPK4 biology and advancing male contraceptive discovery.
SN - 0002-7863
SN - 1520-5126
ER -