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Updated: May 12, 2026
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
A small molecule screen in stem-cell-derived motor neurons identifies a kinase inhibitor as a candidate therapeutic
Yin M Yang1, Shailesh K Gupta, Kevin J Kim
1Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Abstract:
Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease, characterized by motor neuron (MN) death, for which there are no truly effective treatments. Here, we describe a new small molecule survival screen carried out using MNs from both wild-type and mutant SOD1 mouse embryonic stem cells. Among the hits we found, kenpaullone had a particularly impressive ability to prolong the healthy survival of both types of MNs that can be attributed to its dual inhibition of GSK-3 and HGK kinases. Furthermore, kenpaullone also strongly improved the survival of human MNs derived from ALS-patient-induced pluripotent stem cells and was more active than either of two compounds, olesoxime and dexpramipexole, that recently failed in ALS clinical trials. Our studies demonstrate the value of a stem cell approach to drug discovery and point to a new paradigm for identification and preclinical testing of future ALS therapeutics.
Insights
Researchers identified kenpaullone, a novel small molecule, that significantly enhances motor neuron survival in models of amyotrophic lateral sclerosis (ALS). This discovery offers a promising new avenue for developing effective ALS treatments.
Area of Science:
- Neuroscience
- Stem Cell Biology
- Drug Discovery
Background:
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss.
- Current treatments for ALS are limited, highlighting the urgent need for novel therapeutic strategies.
Purpose of the Study:
- To identify novel small molecules that promote motor neuron survival using a stem cell-based drug screening approach.
- To evaluate the efficacy of identified compounds in preclinical models of ALS.
Main Methods:
- A small molecule survival screen was performed using motor neurons derived from wild-type and mutant SOD1 mouse embryonic stem cells.
- The neuroprotective effects of candidate compounds were assessed on human motor neurons from ALS patients.
- Inhibition of GSK-3 and HGK kinases by kenpaullone was investigated.
Main Results:
- Kenpaullone demonstrated significant neuroprotective effects, prolonging the survival of both wild-type and mutant SOD1 mouse motor neurons.
- Kenpaullone treatment also improved the survival of human motor neurons derived from ALS patient-specific induced pluripotent stem cells.
- The compound showed superior efficacy compared to olesoxime and dexpramipexole, which previously failed in ALS clinical trials.
Conclusions:
- Stem cell-based screening is a valuable approach for identifying potential ALS therapeutics.
- Kenpaullone, through dual inhibition of GSK-3 and HGK kinases, represents a promising candidate for future ALS drug development.
- This study establishes a new paradigm for the preclinical testing of ALS therapeutics.
