Inhibition of GCK-IV kinases dissociates cell death and axon regeneration in CNS neurons. 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. Proc Natl Acad Sci U S A. 2020 Dec 29;117(52):33597-33607. doi: 10.1073/pnas.2004683117. Epub 2020 Dec 14. PubMed PMID: 33318207; PubMed Central PMCID: PMC7777023.
In this study, we applied our idTRAX platform in a unique and novel way to a model of glaucoma with our collaborators are UCSD and John's Hopkins. Rather than utilize a single phenotypic assay, our collaborators ran two assays with retinal ganglion neurons (RGCs) - one for neuroprotection and one for neurite outgrowth. This allowed us to identify druggable targets to promote either process. By looking at the intersection of the two sets, the group was able to identify kinases that can be targeted to promote both RGC survival AND axon regeneration (prior to this study, only targets that mediate either process at a time were known). These findings were validated in vivo, thereby creating the foundation for a drug development program targeting glaucoma and other neurodegenerative eye diseases.
Phenotypic Screening Combined with Machine Learning for Efficient Identification of Breast Cancer-Selective Therapeutic Targets. Gautam P, Jaiswal A, Aittokallio T, Al-Ali H, Wennerberg K. Cell Chem Biol. 2019 Jul 18;26(7):970-979.e4. doi: 10.1016/j.chembiol.2019.03.011. Epub 2019 May 2. PubMed PMID: 31056464; PubMed Central PMCID: PMC6642004.
In this study, we applied idTRAX to a variety of triple negative and non-triple negative breast cancer cell lines with our collaborators at the Finland Institute of Molecular Medicine and demonstrated that we can identify drug targets that selectively sensitize specific cancer types. We recapitulated known literature on kinase sensitivities of each cancer type and discovered novel targets that were previously not described. Importantly, we demonstrated how using this approach for target identification we can side step many of the caveats encountered using genetic methods such as RNAi and CRISPR.
The mTOR Substrate S6 Kinase 1 (S6K1) Is a Negative Regulator of Axon Regeneration and a Potential Drug Target for Central Nervous System Injury. Al-Ali H, Ding Y, Slepak T, Wu W, Sun Y, Martinez Y, Xu XM, Lemmon VP, Bixby JL. J Neurosci. 2017 Jul 26;37(30):7079-7095. doi: 10.1523/JNEUROSCI.0931-17.2017. Epub 2017 Jun 16. PubMed PMID: 28626016; PubMed Central PMCID: PMC5546395.
Following the landmark discovery that mTOR is a mediator of axon regeneration, it was long believed that S6 Kinase 1 (S6K1) - a downstream effector of mTOR - is also a mediator of axon regeneration. We showed that the opposite is in fact the case, and that S6K1 functions as a negative feedback regulator of axon regeneration. With our collaborators at Indiana University, we showed that S6K1 inhibition indeed promotes axon regeneration and behavior recovery in an animal model of spinal cord injury. We also showed that this occurs by lifting feedback inhibition on mTOR signaling and consequently stimulating that pathway. These studies established S6K1 as a tractable drug target for promoting CNS regeneration. It is worth noting that this strategy for activating mTOR and promoting axon regeneration in vivo is safer than the alterative approach of inhibiting the tumor suppressor PTEN, which carries a significant risk of causing cancer.
Rational Polypharmacology: Systematically Identifying and Engaging Multiple Drug Targets To Promote Axon Growth. Al-Ali H, Lee DH, Danzi MC, Nassif H, Gautam P, Wennerberg K, Zuercher B, Drewry DH, Lee JK, Lemmon VP, Bixby JL. ACS Chem Biol. 2015 Aug 21;10(8):1939-51. doi: 10.1021/acschembio.5b00289. Epub 2015 Jun 24. PubMed PMID: 26056718; PubMed Central PMCID: PMC4899818.
When this paper came out, the concept of polypharmacology in drug design was still a contentious topic. Since then, the tide has shifted and the idea that polypharmacology is the next frontier in drug development is now mainstream. This paper was amongst the first to pioneer polypharmacology by design outside of oncological applications. It was also amongst the first to advocate kinases as viable drug targets for neurological applications. That too has become more accepted today. Our group has continued to build on the findings of this study and has developed a lead candidate based on the targets initially discovered here. The candidate is currently in pre-clinical development, with projected onset of clinical trials in 2025.