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Updated: May 17, 2025
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
Identification of Novel HPK1 Hit Inhibitors: From In Silico Design to In Vitro Validation
Israa H Isawi1, Rayan M Obeidat1, Soraya Alnabulsi1
1Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan.
Abstract:
Hematopoietic progenitor kinase 1 (HPK1), a negative regulator of T-cells, B-cells, and dendritic cells, has gained attention in antitumor immunotherapy research over the past decade. No HPK1 inhibitor has yet reached clinical approval, largely due to selectivity and drug-like limitations. Leveraging the available structural insights into HPK1, we conducted a rational hit identification using a structure-based virtual screening of over 600,000 drug-like molecules from ASINEX and OTAVA databases. A series of molecular docking studies, in vitro kinase assays, and molecular dynamics simulations were conducted to identify viable HPK1 inhibitor hits. This approach resulted in two promising novel hit scaffolds, 4H-Pyrido[1,2-a] thieno[2,3-d] pyrimidin-4-one (ISR-05) and quinolin-2(1H)-one (ISR-03), neither of which has previously been reported as an HPK1 inhibitor. ISR-05 and ISR-03 exhibited IC50 values of 24.2 ± 5.07 and 43.9 ± 0.134 µM, respectively, in kinase inhibition assays. These hits constitute tractable starting points for future hit-to-lead optimization aimed at developing more effective HPK1 inhibitors for cancer therapy.
Insights
Researchers identified novel inhibitors for Hematopoietic progenitor kinase 1 (HPK1), a key target in cancer immunotherapy. These new compounds show promise for developing more effective cancer treatments by modulating immune cell activity.
Area of Science:
- Immunology
- Pharmacology
- Medicinal Chemistry
Background:
- Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of immune cells, crucial in antitumor immunotherapy.
- Current HPK1 inhibitors face challenges with selectivity and drug-like properties, hindering clinical translation.
- Targeting HPK1 offers a promising strategy for enhancing anti-cancer immune responses.
Purpose of the Study:
- To identify novel, potent inhibitors of Hematopoietic progenitor kinase 1 (HPK1) using structure-based drug design.
- To discover new chemical scaffolds for HPK1 inhibitors with improved drug-like potential.
- To provide starting points for optimizing HPK1 inhibitors for cancer therapy.
Main Methods:
- Structure-based virtual screening of over 600,000 drug-like molecules against HPK1.
- Molecular docking, in vitro kinase inhibition assays, and molecular dynamics simulations were employed.
- Identification and characterization of novel hit scaffolds targeting HPK1.
Main Results:
- Two novel hit scaffolds, 4H-Pyrido[1,2-a] thieno[2,3-d] pyrimidin-4-one (ISR-05) and quinolin-2(1H)-one (ISR-03), were identified.
- ISR-05 and ISR-03 demonstrated inhibitory activity against HPK1 with IC50 values of 24.2 ± 5.07 µM and 43.9 ± 0.134 µM, respectively.
- These scaffolds represent previously unreported chemical classes as HPK1 inhibitors.
Conclusions:
- The identified HPK1 inhibitors (ISR-05 and ISR-03) are promising starting points for drug development.
- Further optimization of these novel scaffolds could lead to effective HPK1-targeted cancer therapies.
- This study advances the development of immunotherapies by providing new chemical matter for HPK1 inhibition.
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