2. Academic Validation
  3. Discovery and Optimization of Pyrrolopyrimidine Derivatives as Selective Disruptors of the Perinucleolar Compartment, a Marker of Tumor Progression toward Metastasis

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

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.

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