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

  • J Med Chem. 2022 Jun 23;65(12):8303-8331. doi: 10.1021/acs.jmedchem.2c00204.
Kevin J Frankowski  1  2 ,  Samarjit Patnaik  3 ,  Chen Wang  4 ,  Noel Southall  3 ,  Dipannita Dutta  3 ,  Soumitta De  5 ,  Dandan Li  5 ,  Christopher Dextras  3 ,  Yi-Han Lin  3 ,  Marthe Bryant-Connah  3 ,  Danielle Davis  3 ,  Feijun Wang  2 ,  Leah M Wachsmuth  3 ,  Pranav Shah  3 ,  Jordan Williams  3 ,  Md Kabir  3 ,  Edward Zhu  3 ,  Bolormaa Baljinnyam  3 ,  Amy Wang  3 ,  Xin Xu  3 ,  John Norton  4 ,  Marc Ferrer  3 ,  Steve Titus  3 ,  Anton Simeonov  3 ,  Wei Zheng  3 ,  Lesley A Mathews Griner  3 ,  Ajit Jadhav  3 ,  Jeffrey Aubé  1  2 ,  Mark J Henderson  3 ,  Udo Rudloff  5 ,  Frank J Schoenen  1 ,  Sui Huang  4 ,  Juan J Marugan  3
Affiliations
  • 1. KU Specialized Chemistry Center, University of Kansas, 2034 Becker Drive, Lawrence, Kansas 66047, United States.
  • 2. Center for Integrative Chemical Biology and Drug Discovery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 3. National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
  • 4. Department of Cell and Molecular Biology, Northwestern University, Chicago, Illinois 60611, United States.
  • 5. Rare Tumor Initiative, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, United States.
PMID: 35696646 DOI: 10.1021/acs.jmedchem.2c00204
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.