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Project

Novel and potent compounds that promote axon growth

Funder: Craig H Neilsen Foundation

Funding period
USD 600 K
Funding amount
Abstract
Over the past fifteen years our group has used phenotypic analysis with different kinds of primary neurons to screen thousands of cDNAs, siRNAs and tens of thousands of compounds to identify agents to treat spinal cord injury. This effort resulted in the identification of transcription factors (TFs) like KLFs, Sox11, STAT3 and kinases as targets for therapeutic development. Using transcription factors to promote axon regeneration could have unintended consequences, such as causing cancer. We have used phenotypic assays with alternative libraries and found much more active agents, i.e. they increase neurite growth in vitro and axon regeneration in vivo to significantly greater extents than individual TFs or combinations of TFs. Because they are small molecules, they can be delivered and withdrawn easily, avoiding many concerns about gene therapy strategies.To identify a wider range of druggable targets and, at the same time, novel compounds we have used a mixture-based approach to screen > 400 million unique compound structures on live primary neurons. At the risk of being annoying, we screened over 400,000,000 compounds on primary neurons. The compounds were screened at 6 doses, ranging from 10 ug/ml to 3.2 ng/ml for each compound. A total of four rounds of screening allowed deconvolution and identification of 9 pure compounds that could promote neurite outgrowth. The compounds were resynthesized and had virtually identical EC50 curves when compared to the original deconvolution data. The five most potent compounds are all active in vitro below 10 nM, a dramatic improvement compared to a selective S6K1 inhibitor, PF-4708671, we have used successfully to promote CST regeneration. They also produce much larger increases in neurite outgrowth than PF-4708671 and transcription factors, such as KLF7 and Stat3. These compounds have been selected for subsequent evaluation based on the high translatability we have demonstrated for our in vitro assay along with their potent bioactivities. We have submitted a provisional patent application to protect the eventual therapeutic development and clinical testing of these compoundsThe proposed experiments will investigate the ability of the 5 most potent compounds to promote axon regeneration and sprouting after a spinal cord injury. They will next test the two most active compounds in vivo in a clinically relevant model of SCI; contusion. Finally, affinity purification methods, combined with Mass Spectrometry will be used to identify the molecular targets of the compounds. Because of the very high potency of the compounds (less than 10 nanomolar), affinity purification methods are very likely to work. We have assembled a very experienced team to maximize the chances for successful conclusions of the experiments. The goal is to push the lead compound into The NINDS Blueprint Neurotherapeutics Network (BPN) for further medicinal chemistry and clinical trials. (CHN: SCIRTS chn:wdg)
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System

Categories
  • FOR (ANZSRC)

    0305 Organic Chemistry

  • RCDC

    Injury (total) Accidents/Adverse Effects

  • RCDC

    Injury - Trauma - (Head and Spine)

  • RCDC

    Biotechnology

  • RCDC

    Regenerative Medicine

  • RCDC

    Neurosciences

  • RCDC

    Spinal Cord Injury

  • RCDC

    Neurodegenerative

  • HRCS RAC

    5.1 Pharmaceuticals

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science