Related Experiment Video

Updated: Jul 13, 2026

High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
05:33

High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines

Published on: November 9, 2020

From inhibition to degradation: advances in highly selective targeting strategies for HPK1

Longbin Yu1, Rui Yan1, Yashi Li1

  • 1Key Laboratory of Natural Medicines of the Changbai Mountain, Yanbian University College of Pharmacy, Ministry of Education, Yanji, 133002, People's Republic of China.

Molecular Diversity
|July 11, 2026
PubMed

Hematopoietic progenitor kinase 1 (HPK1) is a serine/threonine kinase specific to the hematopoietic system. As a member of the mammalian Ste20-related MAP4K kinase family, HPK1 serves as a key negative regulator of T cell-mediated immune responses. It is implicated in the development of human malignancies. Consequently, HPK1 has emerged as a highly promising target for cancer immunotherapy. Inhibition of HPK1 can abrogate its suppressive effects on T cell activation and function. However, HPK1 shares high structural homology with other MAP4K family members, particularly GLK. This poses a major challenge to the development of highly selective inhibitors. Achieving selectivity by distinguishing HPK1 from other family kinases and key T-cell activation kinases is crucial. It helps minimize off‑target side effects and broaden the therapeutic window. This review summarizes advances in HPK1-targeting strategies from 2016 to 2026. Focusing on the structural classes and selectivity optimization mechanisms of highly selective small-molecule HPK1 inhibitors, as well as breakthroughs in the development of proteolysis-targeting chimeras (PROTACs). The structural biology basis underlying HPK1 selectivity regulation is also analyzed. Finally, this review addresses the challenges in developing HPK1-targeted formulations and discusses future research directions, with the aim of providing a reliable reference for the rational design and clinical translation of novel, highly selective HPK1-targeted therapeutic strategies.

Keywords:
Cancer immunotherapyHPK1HPK1 PROTACHPK1 inhibitionKinase selectivity

More Related Videos

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors10:33

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

A Bilingual Computational Workflow for Identifying Potential PLK1 Inhibitors in American Sign Language and English14:34

A Bilingual Computational Workflow for Identifying Potential PLK1 Inhibitors in American Sign Language and English

Published on: April 3, 2026

Related Concept Videos

Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Inhibition of CDK Activity02:34

Inhibition of CDK Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against specific...
Regulated Protein Degradation02:58

Regulated Protein Degradation

It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
M-Cdk Drives Transition Into Mitosis02:15

M-Cdk Drives Transition Into Mitosis

Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...