Kinases and regeneration
Kinases regulate most aspects of cell function. As they are very important in cancer, there are many drugs and compounds as well as cDNA and RNAi libraries that can be used to perturb the Kinome. Neuroscientists should exploit these resources.
We have done a large overexpression screen in primary hippocampal neurons (Buchser et al, 2010). Besides identifying interesting individual targets for further study, we did pathway analysis and gene ontology analysis based on the phenotypic data. Guess what? Cancer pathways are very important in regulating neurite growth.
More recently we are using kinase inhibitors (KIs) to identify target (those to inhibit) and liability (those to avoid) kinases to promote regeneration (Al-Ali et al, 2013). This work exploits polypharmacology and KI biochemical profiling data, Maximum Relevance algorithms and Support Vector Machines, followed by RNAi to design a small but informative list of kinases that can be used to predict whether a new compound will enhance neurite growth (watch this space!). Did I mention Hassan's 5 KI, 4 concentration, all combinations experiment? It is sweet*.
*by this, Vance means informative.
Hassan's development of idTRAX to deconvolve targets using phenotypic screening data and biochemical profiling data of kinase inhibitors has proven a powerful approach for finding efficacious drug targets. In 2022 we received an award from NINDS to turn our best KI hit into a drug: NINDS 1 UH3 NS124630, Developing a kinase inhibitor drug to treat spinal cord injury.
Contact PI: H. Ali. Co-PIs: J. Bixby and V. Lemmon
Slepak TI, Salay LD, Lemmon VP, Bixby JL. Dyrk kinases regulate phosphorylation of doublecortin, cytoskeletal organization, and neuronal morphology. Cytoskeleton (Hoboken). 2012 69:514-27.
Buchser WJ, Slepak TI, Gutierrez-Arenas O, Bixby JL, Lemmon VP. Kinase/phosphatase overexpression reveals pathways regulating hippocampal neuron morphology. Mol Syst Biol. 2010 Jul 27;6:391.PMID: 20664637
Al-Ali H, Schürer SC, Lemmon VP, Bixby JL. Chemical Interrogation of the Neuronal Kinome Using a Primary Cell-Based Screening Assay. ACS Chem Biol. 2013 8:1027-36
Al-Ali H, Lee DH, Danzi MC, Nassif H, Gautam P, Wennerberg K, Zuercher B, Drewry DH, Lee JK, Lemmon VP, Bixby JL. Rational Polypharmacology: Systematically Identifying and Engaging Multiple Drug Targets To Promote Axon Growth. ACS Chem Biol. 2015 10:1939-51. PMID: 26056718
Al-Ali H, Ding Y, Slepak T, Wu W, Sun Y, Martinez Y, Xu XM, Lemmon VP, Bixby JL. The mTOR substrate S6 Kinase 1 (S6K1) is a negative regulator of axon regeneration and a potential drug target for Central Nervous System injury. J Neurosci. 2017 Jun 16. pii: 0931-17. doi: 10.1523/JNEUROSCI.0931-17.2017. PMID: 28626016
Devkota P, Danzi MC, Lemmon VP, Bixby JL, Wuchty S. Computational Identification of Kinases That Control Axon Growth in Mouse. SLAS Discov. 2020 25:792-800. doi: 10.1177/2472555220930697. Epub 2020 Jul 2.PMID: 32613890
Patel AK, Broyer RM, Lee CD, Lu T, Louie MJ, La Torre A, Al-Ali H, Vu MT, Mitchell KL, Wahlin KJ, Berlinicke CA, Jaskula-Ranga V, Hu Y, Duan X, Vilar S, Bixby JL, Weinreb RN, Lemmon VP, Zack DJ, Welsbie DS. Inhibition of GCK-IV kinases dissociates cell death and axon regeneration in CNS neurons. Proc Natl Acad Sci U S A. 2020 Dec 29;117(52):33597-33607. doi: 10.1073/pnas.2004683117. Epub 2020 Dec 14. PMID: 33318207
Mah KM, Wu W, Al-Ali H, Sun Y, Han Q, Ding Y, Muñoz M, Xu XM, Lemmon VP, Bixby JL. Compounds co-targeting kinases in axon regulatory pathways promote regeneration and behavioral recovery after spinal cord injury in mice. Exp Neurol. 2022 May 16;355:114117. doi:10.1016/j.expneurol.2022.114117. PMID: 35588791
We have done a large overexpression screen in primary hippocampal neurons (Buchser et al, 2010). Besides identifying interesting individual targets for further study, we did pathway analysis and gene ontology analysis based on the phenotypic data. Guess what? Cancer pathways are very important in regulating neurite growth.
More recently we are using kinase inhibitors (KIs) to identify target (those to inhibit) and liability (those to avoid) kinases to promote regeneration (Al-Ali et al, 2013). This work exploits polypharmacology and KI biochemical profiling data, Maximum Relevance algorithms and Support Vector Machines, followed by RNAi to design a small but informative list of kinases that can be used to predict whether a new compound will enhance neurite growth (watch this space!). Did I mention Hassan's 5 KI, 4 concentration, all combinations experiment? It is sweet*.
*by this, Vance means informative.
Hassan's development of idTRAX to deconvolve targets using phenotypic screening data and biochemical profiling data of kinase inhibitors has proven a powerful approach for finding efficacious drug targets. In 2022 we received an award from NINDS to turn our best KI hit into a drug: NINDS 1 UH3 NS124630, Developing a kinase inhibitor drug to treat spinal cord injury.
Contact PI: H. Ali. Co-PIs: J. Bixby and V. Lemmon
Slepak TI, Salay LD, Lemmon VP, Bixby JL. Dyrk kinases regulate phosphorylation of doublecortin, cytoskeletal organization, and neuronal morphology. Cytoskeleton (Hoboken). 2012 69:514-27.
Buchser WJ, Slepak TI, Gutierrez-Arenas O, Bixby JL, Lemmon VP. Kinase/phosphatase overexpression reveals pathways regulating hippocampal neuron morphology. Mol Syst Biol. 2010 Jul 27;6:391.PMID: 20664637
Al-Ali H, Schürer SC, Lemmon VP, Bixby JL. Chemical Interrogation of the Neuronal Kinome Using a Primary Cell-Based Screening Assay. ACS Chem Biol. 2013 8:1027-36
Al-Ali H, Lee DH, Danzi MC, Nassif H, Gautam P, Wennerberg K, Zuercher B, Drewry DH, Lee JK, Lemmon VP, Bixby JL. Rational Polypharmacology: Systematically Identifying and Engaging Multiple Drug Targets To Promote Axon Growth. ACS Chem Biol. 2015 10:1939-51. PMID: 26056718
Al-Ali H, Ding Y, Slepak T, Wu W, Sun Y, Martinez Y, Xu XM, Lemmon VP, Bixby JL. The mTOR substrate S6 Kinase 1 (S6K1) is a negative regulator of axon regeneration and a potential drug target for Central Nervous System injury. J Neurosci. 2017 Jun 16. pii: 0931-17. doi: 10.1523/JNEUROSCI.0931-17.2017. PMID: 28626016
Devkota P, Danzi MC, Lemmon VP, Bixby JL, Wuchty S. Computational Identification of Kinases That Control Axon Growth in Mouse. SLAS Discov. 2020 25:792-800. doi: 10.1177/2472555220930697. Epub 2020 Jul 2.PMID: 32613890
Patel AK, Broyer RM, Lee CD, Lu T, Louie MJ, La Torre A, Al-Ali H, Vu MT, Mitchell KL, Wahlin KJ, Berlinicke CA, Jaskula-Ranga V, Hu Y, Duan X, Vilar S, Bixby JL, Weinreb RN, Lemmon VP, Zack DJ, Welsbie DS. Inhibition of GCK-IV kinases dissociates cell death and axon regeneration in CNS neurons. Proc Natl Acad Sci U S A. 2020 Dec 29;117(52):33597-33607. doi: 10.1073/pnas.2004683117. Epub 2020 Dec 14. PMID: 33318207
Mah KM, Wu W, Al-Ali H, Sun Y, Han Q, Ding Y, Muñoz M, Xu XM, Lemmon VP, Bixby JL. Compounds co-targeting kinases in axon regulatory pathways promote regeneration and behavioral recovery after spinal cord injury in mice. Exp Neurol. 2022 May 16;355:114117. doi:10.1016/j.expneurol.2022.114117. PMID: 35588791
| cytoskeleton_2012_slepak.pdf |
| buchser_2010_molecularsystemsbiology.pdf |
| acs_chem._biol._2013_al-ali.pdf |