New allosteric inhibitors for GSK-3 identified for treatment of chronic diseases

Researchers at Centro de Investigaciones Biológicas-CSIC have identified potential candidates for the treatment of chronic rare diseases such as DM1 (myotonic dystrophy type 1) and SMA (spinal muscular atrophy). In a previous work, published in 2011 in J. Med. Chem., an allosteric inhibitor of Glycogen Synthase Kinase 3 (GSK-3) -an enzyme involved in several unmet pathologies- was discovered. Now, a new study has been published in Journal of Medicinal Chemistry which portrays the synthesis of novel allosteric derivatives of GSK-3.

Importantly, the group of Dr. Ana Martinez at CIB studied the molecular pathway upon enzyme inhibition. It was found that the novel allosteric inhibitors avoid potential side effects of GSK-3 inhibition. Therefore, they show promising properties for the treatment of chronic diseases. "This new type of GSK-3 inhibitors have a different molecular behavior than previous ones” Dr. Palomo indicates, suggesting distinctive approaches of enzyme modulation that could be applied to other diseases in which GSK-3 inhibition could be essential for treatment, such as Alzheimer’s disease. The type of inhibition was also confirmed using computational models that revealed that the inhibitors modify the flexibility of the GSK-3 activation loop, decreasing enzyme’s activity.

Once discovered the new mechanism of action of the inhibitors the research team aimed for testing them in chronic diseases using cutting-edge models of neuropathology. “We established collaborations to test our compounds on human models of disease”, said Prof. Martínez. “The models use cells derived from induced pluripotent stem cells, pioneering the way towards more accurate models of disease and reduction of animals in research”. The therapeutic agents were tested in human models of SMA and DM1, two rare neurodegenerative diseases, showing encouraging results.

Overall the findings suggest that the allosteric modulators of GSK-3 may be used for future development of drugs for DM1, SMA or other chronic diseases where GSK-3 inhibition exhibits therapeutic effects.

Reference: Subtly Modulating Glycogen Synthase Kinase 3 β: Allosteric Inhibitor Development and Their Potential for the Treatment of Chronic Diseases. Valle Palomo, Daniel I. Perez, Carlos Roca, Cara Anderson, Natalia Rodríguez-Muela, Concepción Perez, Jose A. Morales-Garcia, Julio A. Reyes, Nuria E. Campillo, Ana M. Perez-Castillo, Lee L. Rubin, Lubov Timchenko, Carmen Gil , Ana Martinez. J. Med. Chem., 2017, 60 (12), pp 4983–5001.