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Combined pharmacophore based small molecule design for direct inhibition of the OLIG2 transcription factor complex. E12 RR VA NN A R E R L R V R D I N E AF K E L G R M CQ L H L --- NS E K P QT K LLIL HQ AV S VIL N L E QQ V 57

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Combined pharmacophore based small molecule design for direct inhibition of the OLIG2 transcription factor complex

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Combined pharmacophore based small molecule design for direct inhibition of the olig2 transcription factor complex

Combined pharmacophore based small molecule design for direct inhibition of the OLIG2 transcription factor complex

E12 RRVANNARERLRVRDINEAFKELGRMCQLHL---NSEKPQTKLLILHQAVSVILNLEQQV 57

HTF4 RRMANNARERLRVRDINEAFKELGRMCQLHL---KSEKPQTKLLILHQAVAVILSLEQQV 57

E47 RRMANNARERVRVRDINEAFRELGRMCQMHL---KSDKAQTKLLILQQAVQVILGLEQQV 57

MyoD3 RRKAATMRERRRLSKVNEAFETLKRSTSSNP---NQRLP--KVEILRNAIRYIEGLQALL 55

MYF5 RRKAATMRERRRLKKVNQAFETLKRCTTTNP---NQRLP--KVEILRNAIRYIESLQELL 55

LYL1 RRVFTNSRERWRQQNVNGAFAELRKLLPTHP--PDRKLS--KNEVLRLAMKYIGFLVRLL 56

TAL2 RKIFTNTRERWRQQNVNSAFAKLRKLIPTHP--PDKKLS--KNETLRLAMRYINFLVKVL 56

MYOG RRRAATLREKRRLKKVNEAFEALKRSTLLNP---NQRLP--KVEILRSAIQYIERLQALL 55

MYF6 RRKAATLRERRRLKKINEAFEALKRRTVANP---NQRLP--KVEILRSAISYIERLQDLL 55

NeuroD1 RRMKANARERNRMHGLNAALDNLRKVVPCYS--KTQKLS--KIETLRLAKNYIWALSEIL 56

OLIG2 LRLKINSRERKRMHDLNIAMDGLREVMPYAHGPSVRKLS--KIATLLLARNYILMLTNSL 58

ATOH1 RRLAANARERRRMHGLNHAFDQLRNVIPSFN--NDKKLS--KYETLQMAQIYINALSETP 56

PTF1 LRQAANVRERRRMQSINDAFEGLRSHIPTLP--YEKRLS--KVDTLRLAIGYINFLSELV 56

HAND2 CAHAGARGGARRTQSINSAFAELRECIPNVP--ADTKLS--KIKTLRLATSYIAYLMDLL 56

HAND1 RKGSGPKKERRRTESINSAFAELRECIPNVP--ADTKLS--KIKTLRLATSYIAYLMDVL 56

TCF21 QRNAANARERARMRVLSKAFSRLKTTLPWVP--PDTKLS--KLDTLRLASSYIAHLRQIL 56

ASCL1 AVARRNERERNRVKLVNLGFATLREHVPNGA--ANKKMS--KVETLRSAVEYIRALQQLL 56

ASCL3 FTRKRNERERQRVKCVNEGYAQLRHHLPEEY--LEKRLS--KVETLRAAIKYINYLQSLL 56

HES5 RRDRINSSIEQLKLLLEQEFARHQ------P---NSKLE--KADILEMAVSYLKHSKGER 49

ID3 GKGPAAEEPLSLLDDMNHCYSRLRELVPGVP--RGTQLS--QVEILQVVLAEPAPGPPDG 56

i

ii

iii

Rajesh Mukthavaram, Igor Tsigelny, Valentina Kouznetsova, Ying Chao, Sandra Pastorino, Jiang Pengfei, Sandeep Pingle, Wolf Wrasidlo, Milan Makale, Santosh KesariMoores Cancer Center, University of California, San Diego, CA.

120

100

■ GBM4

▲ GBM8

▼ U87

♦ NHA

80

% Cell Viability

OBJECTIVES

EXPERIMENTAL RESULTS

CONCLUSIONS

60

40

20

  • Transcription factors (TFs) are a major class of signaling proteins and are key to many diseases

  • Drug design has mostly failed

  • Transformed stem-like cells (CSCs) drive the common and highly lethal brain tumor, glioblastoma

  • Glioblastoma CSCs express high levels of OLIG2, a TF essential for their viability

  • OLIG2 dimerizes with E47 for functional activation, and inhibits P21 gene expression, a tumor suppressor

  • Solution: Targeting the TF, OLIG2 using a novel computational approach based on related, multiple pharmacophores

  • The combined pharmacophore approach defines a parental pharmacophore and multiple daughter pharmacophores (subpharmacophores)

  • NCI database searches yielded structures potentially able to bind all pharmacophores

  • Validation of the combined pharmacophore approach was achieved by the identification and screening of compounds that suppressed human GBM in vitro and suppressed OLIG2 target genes

0

-1.0

0.0

1.0

2.0

Inhibitor conc. log[µM]

Cancer stem like cells, nestin expression

APPROACH

Current Studies

  • Computational modeling of the specific OLIG2–E47 dimerization interface

  • Definition of multiple pharmacophore hypotheses forms the basis of our strategy

  • Searches of conformational databases for compounds predicted to bind all pharmacophores, thus maximizing affinity and specificity

  • Biochemical and cell-based screening and validation of identified compounds

  • Comprehensive investigation and validation

  • of OLIG2 selective binding, using additional

  • biochemical and x-ray crystallographic

  • methods

  • Inhibitors will be further assessed with

  • in vivo GBM models

Homology modeling and definition of the OLIG2 pharmacophore

Sequence alignment of transcription factors binding to E2A

Control

0.5 uM

2.5 uM

Inject

In tribute to Francis X. Colden, III

Acknowledgments

We would like to express our gratitude and sincere appreciation for the American Brain Tumor Foundation and Francis X. Colden, III for their generous grant that made this work possible.

OLIG2 inhibitor effects on expression levels of P21 and OMG

Venn diagram for four sets of

compounds resulted from

Four pharmacophore-hypotheses based search

In-vitro anti-GBM potency of representative compound

In tribute to Francis X. Colden, III


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