Design, Synthesis, and Characterization of Globular Orphan Nuclear Receptor Regulator with Biological Activity in Soft Tissue Sarcoma

Mao Ye, Santosh K. Misra, Arun K. De, Fatemeh Ostadhossein, Kuldeep Singh, Laurie Rund, Lawrence Schook, Dipanjan Pan

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Sarcomas are rare and heterogeneous cancer variants of mesenchymal origin. Their genetic heterogeneity coupled with uncertain histogenesis makes them difficult to treat and results in poor prognosis. In this work, we show that structure-based drug discovery involving computational modeling can be used to identify a new retinoid X receptor (RXR) agonist ligand with a bis(indolyl)methane scaffold. This agent co-self-assembles with an amphiphilic diblock copolymer resulting in nanoparticles (Nano-RXR) with excellent kinetic stability, which were evaluated for efficacy and safety in transformed sarcoma cells, 63-3 Cre and 141-10 Cre of pig origin, and in rodent xenograft models. Responses at gene and protein levels established the treatment approach as a highly effective RXR agonist across cell, rodent, and "Oncopig" models. Interestingly, Nano-RXR was not only able to modulate metabolic and transporter genes related to orphan nuclear receptors but also played a major role in modulating programmed cell death in sarcomas developed in Oncopigs.

Original languageEnglish (US)
Pages (from-to)10739-10752
Number of pages14
JournalJournal of Medicinal Chemistry
Volume61
Issue number23
DOIs
StatePublished - Dec 13 2018

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Fingerprint

Dive into the research topics of 'Design, Synthesis, and Characterization of Globular Orphan Nuclear Receptor Regulator with Biological Activity in Soft Tissue Sarcoma'. Together they form a unique fingerprint.

Cite this