Multiple spatially related pharmacophores define small molecule inhibitors of OLIG2 in glioblastoma
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Igor F. Tsigelny1,2,3,*, Rajesh Mukthavaram3,*, Valentina L. Kouznetsova2,3,*, Ying Chao3, Ivan Babic3, Elmar Nurmemmedov4, Sandra Pastorino3, Pengfei Jiang3, David Calligaris5, Nathalie Agar5, Miriam Scadeng6, Sandeep C. Pingle3, Wolfgang Wrasidlo1,3, Milan T. Makale3 and Santosh Kesari1,3,7
1 Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
2 San Diego Supercomputer Center, University of California San Diego, La Jolla, CA, USA
3 Translational Neuro-oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
4 The Scripps Research Institute, La Jolla, CA, USA
5 Harvard Medical School, Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA, USA
6 FMRI Research Center, Department of Radiology, University of California San Diego, La Jolla, CA, USA
7 Current Address: John Wayne Cancer Institute at Providence Saint John’s Health Center, Santa Monica, CA, USA
* These authors have contributed equally to this work
Igor F. Tsigelny, email:
Santosh Kesari, email:
Keywords: in silico rational drug design, pharmacophore, inhibitor scaffold, transcription factors, OLIG2
Received: September 01, 2015 Accepted: October 14, 2015 Published: October 30, 2015
Transcription factors (TFs) are a major class of protein signaling molecules that play key cellular roles in cancers such as the highly lethal brain cancer—glioblastoma (GBM). However, the development of specific TF inhibitors has proved difficult owing to expansive protein-protein interfaces and the absence of hydrophobic pockets. We uniquely defined the dimerization surface as an expansive parental pharmacophore comprised of several regional daughter pharmacophores. We targeted the OLIG2 TF which is essential for GBM survival and growth, we hypothesized that small molecules able to fit each subpharmacophore would inhibit OLIG2 activation. The most active compound was OLIG2 selective, it entered the brain, and it exhibited potent anti-GBM activity in cell-based assays and in pre-clinical mouse orthotopic models. These data suggest that (1) our multiple pharmacophore approach warrants further investigation, and (2) our most potent compounds merit detailed pharmacodynamic, biophysical, and mechanistic characterization for potential preclinical development as GBM therapeutics.
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