Discovery and Optimization of Pyrrolopyrimidine Derivatives as Selective Disruptors of the Perinucleolar Compartment, a Marker of Tumor Progression toward Metastasis

Frankowski, Kevin J.Patnaik, SamarjitWang, ChenSouthall, NoelDutta, DipannitaDe, SoumitaLi, DandanDextras, ChristopherLin, Yi-HanBryant-Connah, MartheDavis, DanielleWang, FeijunWachsmuth, Leah M.Shah, PranavWilliams, JordanKabir, MdZhu, EdwardBaljinnyam, BolormaaWang, AmyXu, XinNorton, JohnFerrer, MarcTitus, SteveSimeonov, AntonZheng, WeiGriner, Lesley A. MathewsJadhav, AjitAubé, JeffreyHenderson, Mark J.Rudloff, UdoSchoenen, Frank J.Huang, SuiMarugan, Juan J.2023-06-132023-06-132022-06-13Frankowski, 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.2c00204https://hdl.handle.net/1808/34373This 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.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.Copyright © 2022 American Chemical SocietyMetastasisPerinucleolar compartmentPNCMetarrestinNCATS-SM0590Structure-activity relationshipPC3M cellsDiscovery and Optimization of Pyrrolopyrimidine Derivatives as Selective Disruptors of the Perinucleolar Compartment, a Marker of Tumor Progression toward MetastasisArticle10.1021/acs.jmedchem.2c00204https://orcid.org/0000-0002-4265-7620https://orcid.org/0000-0003-4500-880Xhttps://orcid.org/0000-0003-1049-5767https://orcid.org/0000-0001-8590-7338https://orcid.org/0000-0002-3951-7061https://orcid.org/0000-0002-7173-6352PMC10024865openAccess