title: Multiple spatially related pharmacophores define small molecule inhibitors of OLIG2 in glioblastoma.
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.
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.|San Diego Supercomputer Center, University of California San Diego, La Jolla, CA, USA.|Translational Neuro-oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: Igor F
authors.initials: IF
authors.lastname: Tsigelny
authors.affiliation: Translational Neuro-oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Mukthavaram
authors.affiliation: San Diego Supercomputer Center, University of California San Diego, La Jolla, CA, USA.|Translational Neuro-oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: Valentina L
authors.initials: VL
authors.lastname: Kouznetsova
authors.affiliation: Translational Neuro-oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chao
authors.affiliation: Translational Neuro-oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Babic
authors.affiliation: The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Elmar
authors.initials: E
authors.lastname: Nurmemmedov
authors.affiliation: Translational Neuro-oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pastorino
authors.affiliation: Translational Neuro-oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Harvard Medical School, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Calligaris
authors.affiliation: Harvard Medical School, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Agar
authors.affiliation: FMRI Research Center, Department of Radiology, University of California San Diego, La Jolla, CA, USA.
authors.forename: Miriam
authors.initials: M
authors.lastname: Scadeng
authors.affiliation: Translational Neuro-oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: Sandeep C
authors.initials: SC
authors.lastname: Pingle
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.|Translational Neuro-oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wrasidlo
authors.affiliation: Translational Neuro-oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: Milan T
authors.initials: MT
authors.lastname: Makale
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.|Translational Neuro-oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.|Current Address: John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kesari
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001932:Brain Neoplasms / Q000188:drug therapy*; D048708:Cell Growth Processes; D002470:Cell Survival / Q000235:genetics; D003198:Computer Simulation; D015195:Drug Design; D005909:Glioblastoma / Q000188:drug therapy*; D006146:Guanidines / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000076104:Oligodendrocyte Transcription Factor 2; D011485:Protein Binding; D011487:Protein Conformation; D054852:Small Molecule Libraries; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D006146:Guanidines; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D054852:Small Molecule Libraries; C405708:OLIG2 protein, human; C007349:1-(3,4-dichlorophenyl)-3-(4-((1-ethyl-3-piperidyl)amino)-6-methyl-2-pyrimidinyl)guanidine
keywords: OLIG2; in silico rational drug design; inhibitor scaffold; pharmacophore; transcription factors