Covalent inhibitors of the RAS binding domain of PI3Ka impair tumor growth driven by RAS and HER2

Klebba, J. E.; Roy, N.; Bernard, S. M.; Grabow, S.; Hoffman, M. A.; Miao, H.; Tamiya, J.; Wang, J.; Berry, C.; Esparza-Oros, A.; Lin, R.; Liu, Y.; Pariollaud, M.; Parker, H.; Mochalkin, I.; Rana, S.; Snead, A. N.; Walton, E. J.; Wyrick, T. E.; Aitichson, E.; Bedke, K.; Brannon, J. C.; Chick, J. M.; Hee, K.; Horning, B. D.; Ismail, M.; Lamb, K. N.; Lin, W.; Metzger, J.; Pastuszka, M. K.; Pollock, J.; Sigler, J. J.; Tomaschko, M.; Tran, E.; Kinsella, T. M.; Molina-Arcas, M.; Simon, G. M.; Weinstein, D. S.; Downward, J.; Patricelli, M. P.

doi:10.1101/2024.12.17.629001

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bioRxiv · 10.1101/2024.12.17.629001

Covalent inhibitors of the RAS binding domain of PI3Ka impair tumor growth driven by RAS and HER2

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Abstract

Genetic disruption of the RAS binding domain (RBD) of PI 3-kinase (PI3K) prevents the growth of mutant RAS driven tumors in mice and does not impact PI3Ks role in insulin mediated control of glucose homeostasis. Selectively blocking the RAS-PI3K interaction may represent an attractive strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3K lipid kinase activity such as alpelisib. Here we report compounds that bind covalently to cysteine 242 in the RBD of PI3K p110 and block the ability of RAS to activate PI3K activity. These inhibitors have a profound impact on the growth of RAS mutant and also HER2 over-expressing tumors, particularly when combined with other inhibitors of the RAS/MAPK pathway, without causing hyperglycemia.

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Klebba, J. E., Roy, N., Bernard, S. M., Grabow, S., Hoffman, M. A., Miao, H., Tamiya, J., Wang, J., Berry, C., Esparza-Oros, A., Lin, R., Liu, Y., Pariollaud, M., Parker, H., Mochalkin, I., Rana, S., Snead, A. N., Walton, E. J., Wyrick, T. E., Aitichson, E., Bedke, K., Brannon, J. C., Chick, J. M., Hee, K., Horning, B. D., Ismail, M., Lamb, K. N., Lin, W., Metzger, J., Pastuszka, M. K., Pollock, J., Sigler, J. J., Tomaschko, M., Tran, E., Kinsella, T. M., Molina-Arcas, M., Simon, G. M., Weinstein, D. S., Downward, J., Patricelli, M. P.. 2024-12-20. Covalent inhibitors of the RAS binding domain of PI3Ka impair tumor growth driven by RAS and HER2. https://doi.org/10.1101/2024.12.17.629001

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