Stanley Center Therapeutics comprises three integrated research groups with expertise in neuroscience, synaptic biology, electrophysiology, ion channels, assay development, high-throughput screening, structural biology, medicinal chemistry, and drug discovery. We work internally and with the rest of the Stanley Center to understand the impact of disease-linked genes and their variants on neuronal and behavioral function in order to develop new therapeutic hypotheses, nominate drug targets, and seed new drug discovery projects.
CaV3.3 Calcium Channels
CACNA1I, a gene that encodes the T-type calcium channel CaV3.3, has been implicated in schizophrenia through both common variants (i.e., GWAS) and rare variants (i.e., de novo) genetic studies. CACNA1I is highly expressed in the thalamic reticular nucleus (TRN), an area that plays a critical role in sensory gating and processing and sleep. To understand the impact of disease-linked CACNA1I variants, we are analyzing their effect on CaV3.3 channel function using biochemistry and electrophysiology assays and their impact on TRN function in a mouse with a disease-related point mutation. To translate these results into a therapeutic project, we are performing early stage drug discovery for the development of specific modulators of CaV3.3. We have recently concluded a high-throughput compound screen, and we are advancing selected hits into medicinal chemistry optimization.
NaV1.2 Sodium Channels
SCN2A encodes the NaV1.2 sodium channel that plays a major role in action potential generation throughout the brain and has been implicated in multiple central nervous system disorders, including intellectual disability, autism, and epilepsy. We are working with Stanley Center geneticists to identify specific variants identified in these different disorders and performing computational modeling to make predictions of the effect of these variants on channel function. We are then examining the effects of these variants on channel function using biochemistry and electrophysiological methods in heterologous cell lines and neurons. We are developing assays for the identification of modulators of NaV1.2 channel function that we can advance into our medicinal chemistry and drug discovery pipeline.
Synapse Biochemistry in Psychiatric Disease
The genetics of psychiatric disease point to altered synaptic function as playing a critical role in pathogenesis. We are undertaking an effort to identify the effects of disease-linked genes and their exome variants on biochemical signaling that occurs during synaptic plasticity. Ultimately, the goal is to identify convergent biochemical pathways disrupted with multiple genetic perturbations that can point to therapeutic approaches through the rescue of these pathways with small molecule modulators. To do so, we are combining several efforts: 1) the development of methods for performing genetic perturbations in post-mitotic cultured neurons; 2) the identification and validation of biochemical pathways activated during synaptic plasticity in collaboration with the Proteomics Platform at the Broad; and 3) the development of ultra high-content imaging assays for reading out multiple biochemical pathways in parallel using high-resolution imaging systems in collaboration with Mark Bathe’s lab at MIT and the Imaging Platform at Broad.
Activated Microglia PET Ligand
Aberrant pruning of synapses has been implicated in a number of central nervous system disorders, including Huntington's disease, Alzheimer's disease, and schizophrenia, and this pruning is thought to result from the engulfment of synapses by activated microglia. Recent work from the Stanley Center suggests that over activation of the complement pathway and the resulting enhanced synapse pruning may play a role in schizophrenia pathogenesis (Sekar et al., 2016). Therefore, having a tool to measure the activation of microglia in patients would be powerful for the longitudinal analyze of synapse pruning and as a biomarker for therapeutic efficacy. To this end, we are collaborating with Jacob Hooker from MGH and Beth Stevens at HMS to develop PET ligands to specifically mark activated microglia.
Paralog Selective Inhibitor of Glycogen Synthase Kinase 3 and their Use in Psychiatric Disorders
The Stanley Center Therapeutics team has discovered the first isoform selective inhibitors of GSK3α or GSK3β. Exploiting a single amino acid difference within the ATP binding domain, we have developed novel, brain penetrant inhibitors that demonstrate:
- Potent inhibition of GSK3α or GSK3β (nM)
- >10x selectivity for GSK3α or GSK3β
- Unprecedented kinome selectivity (> 100x selectivity vs 311 kinases) due to a distinct kinase chemotype
- A unique hinge binding mode in the ATP pocket
- GSK3α or GSK3β functional selectivity in multiple cell based systems
- Full inhibition of GSK3α or GSK3β enzymatic activity with no effects on β-catenin levels
- Good drug-like properties
- In vivo proof of concept in Fragile X Syndrome and mood-related behavioral models
- Excellent tolerability in acute and chronic dosing paradigms
With the first ever isoform selective inhibitors of GSK3α or GSK3β that successfully decouple effects on β-catenin, we have enabled a unique approach to target these well-trodden kinases in a variety of disease indications where others have failed due to dose-limiting toxicities. Please contact Flo Wagner for additional information.
First in Class β‐arrestin biased D2R antagonist
In 2005, Marc Caron’s lab demonstrated the importance of β‐arrestin 2 signaling downstream of the D2 receptor (D2R) in hyperactivity phenotypes using mouse genetics. Since, scientists within Stanley Center Therapeutics have developed the first small molecule pharmacological tool, a β‐arrestin biased D2R antagonist. The lead compound (BRD5814) demonstrates:
- Potent orthosteric antagonist activity at D2R/ β‐arrestin (0.5 µM in cells)
- No antagonist activity at D2R/Gi‐cAMP signaling pathway
- Better D2R selectivity vs other G‐protein linked seven‐transmembrane domain receptors compared to other antipsychotics (>50 receptors tested)
- Good drug‐like properties (B/P > 5 in rodents, T1/2 > 4hrs in rodent brain, F = 21% in rat)
- Dose‐dependent target engagement in the rat brain (PET imaging)
- In vivo proof of concept in the amphetamine induced hyperlocomotion (AIH) assay
- No motoric side effects at efficacious dose (rotarod assay)
With the first β‐arrestin biased D2R antagonist, our program offers a unique approach to target the well validated dopamine signaling pathway, by retaining D2 mediated antipsychotic efficacy while reducing the risk for various side effects. We welcome collaborations for therapeutic exploration in relevant indications. Please contact Flo Wagner for additional information.
Histone Deacetylase (HDAC) Inhibitors
Modulation of histone deacetylase (HDAC) activity has been implicated as a potential therapeutic strategy for multiple diseases. However, it has been difficult to dissect the role of individual HDACs due to a lack of selective small-molecule inhibitors. Scientists within Stanley Center Therapeutics have rationally designed and developed a series of highly potent and isoform-selective HDAC inhibitors. These series of HDAC inhibitors will enable the study of the role of each individual HDACs in biology. We welcome collaborations for therapeutic exploration in relevant indications. Please contact Flo Wagner for additional information.