Schrödinger is excited to be participating in the Chinese Medicinal Chemistry Symposium and CPA-EFMC Symposium taking place on October 7th-10th in Chongqing, China. Join us for a presentation by Jianxin Duan, Fellow in Applications Science at Schrödinger, titled “In Silico Driven Discovery of Potent, Selective and Brain-penetrant DLK Inhibitors for the Treatment of Neurodegenerative Diseases”.

Speaker: Jianxin Duan, Fellow, Applications Science
Abstract: 
Dual leucine zipper kinase (DLK) (also known as MAP3K12) is a member of the mixed lineage kinase (MLK) family that contains an N-terminal kinase domain followed by two leucine zipper domains and a glycine/serine/proline rich C-terminal domain. It is expressed primarily in neuronal cells, specifically in the synaptic terminal and axon of neurons. Injury to neurons or other cellular stress leads to DLK dimerization, autophosphorylation, phosphorylation of MKK7 and JNK pathway activation. Recent work has demonstrated that genetic deletion or pharmacological inhibition of DLK results in attenuation of synapse loss, neuronal degeneration, and functional decline in models of both Alzheimer’s Disease and Amyotrophic Lateral Sclerosis (ALS), making DLK an attractive therapeutic target for the treatment of neurodegenerative diseases. 
The program execution leveraged Schrödinger’s free energy perturbation (FEP+) technology to prospectively predict compound binding affinity to hDLK and prioritize design ideas that were either hand drawn or generated by AutoDesigner, our proprietary enumeration algorithm. In the Hit-Finding stage, starting from a minimal hinge binding fragment, monocyclic and bicyclic cores were modeled and evaluated by FEP+ using available DLK co-crystal structure. A focused set of ligands with favorable potency predictions were synthesized, resulting in the identification of multiple novel, nanomolar starting points within the first 2 months of program initiation. Further SAR exploration on the top cores by R-group enumeration allowed for the identification of the most promising lead series as well as multiple backup series. During the lead optimization stage, combining FEP+ technology and predictive ADMET modeling tools, including our recently published energy of solvation (E-sol) method for predicting Kp,uu, the team established an efficient work flow to mitigate multiple challenges such as CNS penetration, hERG inhibition, cytotoxicity and selectivity. This resulted in the identification of potent, selective and brain-penetrant dual leucine zipper kinase (DLK) inhibitors, which showed neuroprotective properties in ex vivo axon fragmentation assays and demonstrated dose-dependent p-c-Jun reduction in in vivo mouse cerebellum PD models.