Multiple spatially related pharmacophores define small molecule inhibitors of OLIG2 in glioblastoma.

// Igor F. Tsigelny 1,2,3,* , Rajesh Mukthavaram 3,* , Valentina L. Kouznetsova 2,3,* , Ying Chao 3 , Ivan Babic 3 , Elmar Nurmemmedov 4 , Sandra Pastorino 3 , Pengfei Jiang 3 , David Calligaris 5 , Nathalie Agar 5 , Miriam Scadeng 6 , Sandeep C. Pingle 3 , Wolfgang Wrasidlo 1,3 , Milan T. Makale 3 and Santosh Kesari 1,3,7 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 Correspondence to: 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 Abstract 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.