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J Med Chem. 2018 Nov 14. doi: 10.1021/acs.jmedchem.8b01387. [Epub ahead of print]

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

Ye M1, Misra SK1, De AK2,3, Ostadhossein F1, Singh K4, Rund L2,3,4, Schook L2,3,4, Pan D1,5,6,7,8.

Author information

1
Department of Bioengineering , University of Illinois at Urbana-Champaign , Urbana , Illinois 61801 , United States.
2
Department of Animal Sciences , University of Illinois at Urbana-Champaign , Urbana , Illinois 61801 , United States.
3
Agricultural Animal Care and Use Program , University of Illinois at Urbana-Champaign , Urbana , Illinois 61801 , United States.
4
Veterinary Diagnostic Laboratory , University of Illinois at Urbana-Champaign , Urbana , Illinois 61801 , United States.
5
Beckman Institute of Advanced Science and Technology , University of Illinois at Urbana-Champaign , Urbana , Illinois 61801 , United States.
6
Mills Breast Cancer Institute , Carle Foundation Hospital , 502 N. Busey , Urbana , Illinois 61801 , United States.
7
Department of Materials Science and Engineering , University of Illinois at Urbana-Champaign , Urbana , Illinois 61801 , United States.
8
Carle-Illinois College of Medicine , Urbana , Illinois 61801 , United States.

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.

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