Integrating Artificial Intelligence and Traditional Screens for Targeting “Undruggable" Cancer Targets

My lab is directing major proteomics/chemical genomics projects to map how integral membrane proteins interact to produce either healthy or diseased cells, to identify novel therapeutic targets, and to screen for novel drugs using artificial intelligence platforms, in particular to target lung, colon and pancreatic cancer.

During my talk I'll present our recent unpublished data showing the integration of AI-driven computational tools with two high-throughput, live-cell drug discovery technologies recently developed in my lab - Mammalian Membrane Two-Hybrid Drug Screening (MaMTH-DS) and Split Intein Mediated Protein Ligation (SIMPL).

By progressively screening a cohort of currently ‘undruggable’ protein targets such as KRAS, we obtained valuable prospective validation of our integrated platform and rapidly discovered actionable compounds, establishing a robust pipeline against challenging disease targets associated with untreatable cancers.

References

1. Saraon, P., Snider, J., Kalaidzidis, Y., Wybenga-Groot, L., E., Weiss, K., Rai, A., Radulovich, N., Drecun, L., Vučković, N., Vučetić, A., Wong, V., Thériault, B., Nhu-An Pham, Park, J.H., Datti, A., Wang, J., Pathmanathan, S., Aboualizadeh, F., Lyakisheva, A., Yao, Z., Wang, Y., Joseph, B., Aman, A., Moran, M.F., Prakesch, M., Poda, G., Marcellus, R., Uehling, D., Samaržija, M., Jakopović, M., Tsao, M-S., Shepherd, F.A., Sacher, A., Leighl, N., Akhmanova, A., Al-awar, R., Zerial, M., and Stagljar, I. (2020) A drug discovery platform to identify compounds that inhibit EGFR triple mutants, Nature Chemical Biology 16(5): 577-586. doi: 10.1038/s41589-020-0484-2

2. Yao, Z., Aboualizadeh F., Kroll, J., Akula, I., Snider, J., Lyakisheva, A. Tang, P., Kotlyar, M., Jurisica, I., Boxem, M., and Stagljar, I. (2020) Split Intein Mediated Protein Ligation (SIMPL), a method for detecting protein-protein interactions and their inhibition, Nature Communications 2020 May 15;11(1): 2440. doi: 10.1038/s41467-020-16299-1

3. Saraon P, Snider J, Schormann W, Rai A, Radulovich N, Sánchez-Osuna M, Coulombe-Huntington J, Huard C, Mohammed M, Lima-Fernandes E, Thériault B, Halabelian L, Chan M, Joshi D, Drecun L, Yao Z, Pathmanathan S, Wong V, Lyakisheva A, Aboualizadeh F, Niu L, Li F, Kiyota T, Subramanian R, Joseph B, Aman A, Prakesch M, Isaac M, Mamai A, Poda G, Vedadi M, Marcellus R, Uehling D, Leighl N, Sacher A, Samaržija M, Jakopović M, Arrowsmith C, Tyers M, Tsao MS, Andrews D, Al-Awar R, Stagljar I. (2021) Chemical genetics screen identifies COPB2 tool compounds that alters ER stress response and induces RTK dysregulation in lung cancer cells, Journal of Molecular Biology 433(23):167294. doi: 10.1016/j.jmb.2021.167294.

4. Lim, SH, Snider, J., Birimberg-Schwartz, L., Ip, W., Serralha, J.C., Botelho, H.M., Lopes-Pacheco, M., Pinto, M.C., Moutaoufik, M.T., Zilocchi, M., Laselva, O., Esmaeili, M., Kotlyar, M., Lyakisheva, A., Tang, P., López Vázquez, L., Akula, I., Aboualizadeh, F., Wong, V., Grozavu, I., Opacak- Bernardi, T., Yao, Z., Babu, M., Jurisica, I., Gonska, T., Bear, C.E, Amaral, M.D., Stagljar, I. (2022) CFTR Interactome Mapping Using the Mammalian Membrane Two-Hybrid High-Throughput Screening System, Molecular Systems Biology 18(2):e10629. doi: 10.15252/msb.202110629.