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Optimization of Small molecules inhibitors against hnRNP A18, a regulator of protein translation and an immune checkpoint
Author
Solano-Gonzalez, EduardoFletcher, Steven
Yu, Wenbo
MacKerell, Alexander D., Jr.
Weber, David J., Ph.D.
Carrier, France
Date
2022-06-09Type
Poster/Presentation
Metadata
Show full item recordAbstract
We have identified the heterogenous ribonucleoprotein A18 (hnRNP A18) as a regulator of protein translation in cancer cells. hnRNP A18 recognizes a specific RNA signature motif in the 3’UTR of transcripts associated with cancer cells progression as well as CTLA-4, an immune checkpoint. Tissue micro arrays performed on human cancers indicate that hnRNP A18 is over expressed in 40 to 60% of malignant tissue as compared to normal adjacent tissue. Most importantly, down regulation of hnRNP A18 significantly reduces tumor growth in two mouse xenograft models (melanoma and breast cancer). These data indicate that hnRNP A18 is a valid target for anticancer drug development. To this Aim we first solved hnRNP A18 3D structure by NMR and crystallography and then used Computer assisted Drug design to search for potential hnRNP A18 small molecule binders targeting the RNA binding pocket. Four lead compounds that specifically target hnRNP A18 were identified. The compounds compete out hnRNP A18 RNA binding activity and specifically kill cancer cells expressing hnRNP A18 without affecting normal epithelial cells or cancer cells that do not express hnRNP A18. In vitro pharmacokinetics assay however indicate that the compounds are unstable in mouse plasma thus precluding their use into animal models. Three of the lead compounds share a common feature: they are all phenolic esters, and so it is not surprising that they have very limited half-lives in plasma. A three-pronged Medicinal chemistry strategy was then used to improve the compounds stability. First, amide congeners of the ester parent drugs were prepared, second the corresponding phenol metabolites were synthetized, and third five bulky sterically hindered esters analogues of the parent drugs were synthetized. In all, twenty derivatives were synthetized and analyzed by RNA band shift and cell viability. While most derivatives were able to compete out hnRNP A18 RNA binding activity, three analogues remain as potent or slightly better at killing cancer cells than the parent compounds. An in vitro pharmacokinetics assay was then performed on one of the ester derivatives. Our data indicate that the half-life of the ester derivative increased by ten-fold as compared to the parent compound in mouse plasma. This compound is currently being scaled up for efficacy experiments in mouse models including xenografts and syngeneic models to determine its effect on tumor immune response.Description
Poster presented at the 12th Annual Cancer Biology Research Retreat, June 9, 2022Rights/Terms
Attribution-NonCommercial-NoDerivatives 4.0 InternationalIdentifier to cite or link to this item
http://hdl.handle.net/10713/19129Collections
The following license files are associated with this item:
- Creative Commons
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International