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Discovery and Optimization of Pyrrolopyrimidine Derivatives as Selective Disruptors of the Perinucleolar Compartment, a Marker of Tumor Progression toward Metastasis
Frankowski, Kevin J. Patnaik, Samarjit Wang, Chen Southall, Noel Dutta, Dipannita De, Soumita Li, Dandan Dextras, Christopher Lin, Yi-Han Bryant-Connah, Marthe
Frankowski, Kevin J.
Patnaik, Samarjit
Wang, Chen
Southall, Noel
Dutta, Dipannita
De, Soumita
Li, Dandan
Dextras, Christopher
Lin, Yi-Han
Bryant-Connah, Marthe
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Abstract
The perinucleolar compartment (PNC) is a dynamic subnuclear body found at the periphery of the nucleolus. The PNC is enriched with RNA transcripts and RNA-binding proteins, reflecting different states of genome organization. PNC prevalence positively correlates with cancer progression and metastatic capacity, making it a useful marker for metastatic cancer progression. A high-throughput, high-content assay was developed to identify novel small molecules that selectively reduce PNC prevalence in cancer cells. We identified and further optimized a pyrrolopyrimidine series able to reduce PNC prevalence in PC3M cancer cells at submicromolar concentrations without affecting cell viability. Structure–activity relationship exploration of the structural elements necessary for activity resulted in the discovery of several potent compounds. Analysis of in vitro drug-like properties led to the discovery of the bioavailable analogue, metarrestin, which has shown potent antimetastatic activity with improved survival in rodent models and is currently being evaluated in a first-in-human phase 1 clinical trial.
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This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, Copyright © 2022 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.jmedchem.2c00204.
Date
2022-06-13
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American Chemical Society
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Keywords
Metastasis, Perinucleolar compartment, PNC, Metarrestin, NCATS-SM0590, Structure-activity relationship, PC3M cells
Citation
Frankowski, K. J., Patnaik, S., Wang, C., Southall, N., Dutta, D., De, S., Li, D., Dextras, C., Lin, Y. H., Bryant-Connah, M., Davis, D., Wang, F., Wachsmuth, L. M., Shah, P., Williams, J., Kabir, M., Zhu, E., Baljinnyam, B., Wang, A., Xu, X., … Marugan, J. J. (2022). Discovery and Optimization of Pyrrolopyrimidine Derivatives as Selective Disruptors of the Perinucleolar Compartment, a Marker of Tumor Progression toward Metastasis. Journal of medicinal chemistry, 65(12), 8303–8331. https://doi.org/10.1021/acs.jmedchem.2c00204