A complex task? Direct modulation of transcription factors with small molecules.

Transcription factors with aberrant activity in disease are promising yet untested targets for therapeutic development, particularly in oncology. Directly inhibiting or activating the function of a transcription factor requires specific disruption or recruitment of protein-protein or protein-DNA interactions. The discovery or design of small molecules that specifically modulate these interactions has thus far proven to be a significant challenge and the protein class is often perceived to be 'undruggable.' This review will summarize recent progress in the development of small-molecule probes of transcription factors and provide evidence to challenge the notion that this important protein class is chemically intractable.

[1]  R. Heyman,et al.  The flip side: Identifying small molecule regulators of nuclear receptors. , 2004, Chemistry & biology.

[2]  D. Boger,et al.  Small-molecule antagonists of Myc/Max dimerization inhibit Myc-induced transformation of chicken embryo fibroblasts , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[3]  J. V. Moran,et al.  Initial sequencing and analysis of the human genome. , 2001, Nature.

[4]  M. Gerstein,et al.  Structure and evolution of transcriptional regulatory networks. , 2004, Current opinion in structural biology.

[5]  A. Üren,et al.  Small molecule selected to disrupt oncogenic protein EWS-FLI1 interaction with RNA Helicase A inhibits Ewing's Sarcoma , 2009, Nature Medicine.

[6]  A. Follis,et al.  Small-molecule perturbation of competing interactions between c-Myc and Max. , 2009, Bioorganic & medicinal chemistry letters.

[7]  Stuart L Schreiber,et al.  Discovery of an inhibitor of a transcription factor using small molecule microarrays and diversity-oriented synthesis. , 2003, Journal of the American Chemical Society.

[8]  Yanhong Shi,et al.  Orphan nuclear receptors in drug discovery. , 2007, Drug discovery today.

[9]  M. Mann,et al.  Therapeutic applications of transcription factor decoy oligonucleotides. , 2000, The Journal of clinical investigation.

[10]  M. Henriksson,et al.  Myc Overexpression Enhances Apoptosis Induced by Small Molecules , 2006, Cell cycle.

[11]  T. Berg.  Signal Transducers and Activators of Transcription as Targets for Small Organic Molecules , 2008, ChemBioChem.

[12]  Chinmay Y. Majmudar,et al.  Amphipathic small molecules mimic the binding mode and function of endogenous transcription factors. , 2009, ACS chemical biology.

[13]  A. Parent,et al.  Alternative inhibition of androgen receptor signaling: peptidomimetic pyrimidines as direct androgen receptor/coactivator disruptors. , 2009, ACS chemical biology.

[14]  W. Guida,et al.  Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity , 2007, Proceedings of the National Academy of Sciences.

[15]  Hong Ma,et al.  A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected]. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[16]  S. Gery,et al.  Transcription factors in hematopoietic malignancies. , 2007, Current Opinion in Genetics and Development.

[17]  Landon R. Whitby,et al.  Small molecule inhibitors of Myc/Max dimerization and Myc-induced cell transformation. , 2009, Bioorganic & medicinal chemistry letters.

[18]  S. Bressman,et al.  Mutations in the THAP1 gene are responsible for DYT6 primary torsion dystonia , 2009, Nature Genetics.

[19]  Bianca Sperl,et al.  Selective Inhibition of c‐Myc/Max Dimerization by a Pyrazolo[1,5‐a]pyrimidine , 2007, ChemMedChem.

[20]  J. Rowley,et al.  The critical role of chromosome translocations in human leukemias. , 1998, Annual review of genetics.

[21]  B. Johansson,et al.  The impact of translocations and gene fusions on cancer causation , 2007, Nature Reviews Cancer.

[22]  K. Asadullah,et al.  Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[23]  P. Vogt,et al.  A credit-card library approach for disrupting protein-protein interactions. , 2006, Bioorganic & medicinal chemistry.

[24]  Valerie Daggett,et al.  Principles of ligand binding within a completely buried cavity in HIF2alpha PAS-B. , 2009, Journal of the American Chemical Society.

[25]  C. Craik,et al.  Trapping Moving Targets with Small Molecules , 2009, Science.

[26]  Stephen K. Burley,et al.  X-Ray Structures of Myc-Max and Mad-Max Recognizing DNA Molecular Bases of Regulation by Proto-Oncogenic Transcription Factors , 2003, Cell.

[27]  J. Katzenellenbogen,et al.  Synthesis and biological evaluation of guanylhydrazone coactivator binding inhibitors for the estrogen receptor. , 2008, Bioorganic & Medicinal Chemistry.

[28]  Kevin H. Gardner,et al.  Artificial ligand binding within the HIF2α PAS-B domain of the HIF2 transcription factor , 2009, Proceedings of the National Academy of Sciences.

[29]  Raymond E. Moellering,et al.  Direct inhibition of the NOTCH transcription factor complex , 2009, Nature.

[30]  Ariele Viacava Follis,et al.  Multiple independent binding sites for small-molecule inhibitors on the oncoprotein c-Myc. , 2009, Journal of the American Chemical Society.

[31]  I. Bozzoni,et al.  Heterochromatic gene repression of the retinoic acid pathway in acute myeloid leukemia. , 2007, Blood.

[32]  P. Baráth,et al.  Identification of small molecule regulators of the nuclear receptor HNF4alpha based on naphthofuran scaffolds. , 2009, Bioorganic & medicinal chemistry.

[33]  J. Darnell.  Transcription factors as targets for cancer therapy , 2002, Nature Reviews Cancer.

[34]  Hui Wang,et al.  Direct inhibition of hypoxia-inducible transcription factor complex with designed dimeric epidithiodiketopiperazine. , 2009, Journal of the American Chemical Society.

[35]  A. Parent,et al.  Blocking estrogen signaling after the hormone: pyrimidine-core inhibitors of estrogen receptor-coactivator binding. , 2008, Journal of medicinal chemistry.

[36]  R. Tjian,et al.  Coactivator cross-talk specifies transcriptional output. , 2006, Genes & development.

[37]  Judith M. Müller,et al.  Discovery of Chromone‐Based Inhibitors of the Transcription Factor STAT5 , 2008, Chembiochem : a European journal of chemical biology.

[38]  Hans‐Dieter Arndt.  Small molecule modulators of transcription. , 2006, Angewandte Chemie.

[39]  T. Berg.  Inhibition of transcription factors with small organic molecules. , 2008, Current opinion in chemical biology.

[40]  P. Dervan,et al.  Modulating hypoxia-inducible transcription by disrupting the HIF-1-DNA interface. , 2007, ACS chemical biology.

[41]  John S Lazo,et al.  Low molecular weight inhibitors of Myc–Max interaction and function , 2003, Oncogene.

[42]  D. Scudiero,et al.  A high-throughput fluorescence-anisotropy screen that identifies small molecule inhibitors of the DNA binding of B-ZIP transcription factors. , 2005, Analytical biochemistry.

[43]  P. Schultz,et al.  A small molecule primes embryonic stem cells for differentiation. , 2009, Cell stem cell.

[44]  Renxiao Wang,et al.  A low-molecular-weight compound discovered through virtual database screening inhibits Stat3 function in breast cancer cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[45]  Richard A Gibbs,et al.  Genomic analysis of the nuclear receptor family: new insights into structure, regulation, and evolution from the rat genome. , 2004, Genome research.

[46]  A. Monks,et al.  Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. , 2005, Cancer research.

[47]  M. Henriksson,et al.  Identification of small molecules that induce apoptosis in a Myc-dependent manner and inhibit Myc-driven transformation. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[48]  Huafeng Zhang,et al.  Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization , 2009, Proceedings of the National Academy of Sciences.

[49]  Chinmay Y. Majmudar,et al.  Chemical approaches to transcriptional regulation. , 2005, Current opinion in chemical biology.

[50]  J. Hirschhorn,et al.  Supporting Online Material Materials and Methods Figs. S1 to S10 Tables S1 to S7 References Human Fetal Hemoglobin Expression Is Regulated by the Developmental Stage-specific Repressor Bcl11a , 2022 .

[51]  Eugene Bolotin,et al.  Identification of an Endogenous Ligand Bound to a Native Orphan Nuclear Receptor , 2009, PloS one.

[52]  A. Koehler,et al.  Small-molecule microarrays as tools in ligand discovery. , 2008, Chemical Society reviews.

[53]  E. Prochownik,et al.  Efficacy, pharmacokinetics, tisssue distribution, and metabolism of the Myc–Max disruptor, 10058-F4 [Z,E]-5-[4-ethylbenzylidine]-2-thioxothiazolidin-4-one, in mice , 2009, Cancer Chemotherapy and Pharmacology.

[54]  William P. Katt,et al.  An oxazole-based small-molecule Stat3 inhibitor modulates Stat3 stability and processing and induces antitumor cell effects. , 2007, ACS chemical biology.

[55]  G. Melillo,et al.  Development of HIF-1 inhibitors for cancer therapy , 2009, Journal of cellular and molecular medicine.

[56]  P. Yue,et al.  Disruption of Transcriptionally Active Stat3 Dimers with Non‐phosphorylated, Salicylic Acid‐Based Small Molecules: Potent in vitro and Tumor Cell Activities , 2009, Chembiochem : a European journal of chemical biology.

[57]  William P. Katt,et al.  Isoform selective inhibition of STAT1 or STAT3 homo-dimerization via peptidomimetic probes: structural recognition of STAT SH2 domains. , 2007, Bioorganic & medicinal chemistry letters.

[58]  Marc S. Cortese,et al.  Rational drug design via intrinsically disordered protein. , 2006, Trends in biotechnology.

[59]  A. Brivanlou,et al.  Signal Transduction and the Control of Gene Expression , 2002, Science.

[60]  J. Katzenellenbogen,et al.  Amphipathic benzenes are designed inhibitors of the estrogen receptor alpha/steroid receptor coactivator interaction. , 2008, ACS chemical biology.

[61]  I. Bahar,et al.  Discovery of novel Myc-Max heterodimer disruptors with a three-dimensional pharmacophore model. , 2009, Journal of medicinal chemistry.

[62]  Dirk Eick,et al.  Selective inhibition of c-Myc/Max dimerization and DNA binding by small molecules. , 2006, Chemistry & biology.

[63]  Bruce R Donald,et al.  Allosteric inhibition of the protein-protein interaction between the leukemia-associated proteins Runx1 and CBFbeta. , 2007, Chemistry & biology.

[64]  K. Gardner,et al.  Identification of small-molecule antagonists that inhibit an activator: coactivator interaction. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[65]  E. Prochownik,et al.  MYC oncogenes and human neoplastic disease , 1999, Oncogene.

[66]  R. Shoemaker,et al.  Targeting the PAS-A Domain of HIF-1α for Development of Small Molecule Inhibitors of HIF-1 , 2006, Cell cycle.

[67]  D. Livingston,et al.  Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway. , 2004, Cancer cell.

[68]  Ariele Viacava Follis,et al.  Structural rationale for the coupled binding and unfolding of the c-Myc oncoprotein by small molecules. , 2008, Chemistry & biology.

[69]  T. Kodadek,et al.  A cell-permeable synthetic transcription factor mimic. , 2007, Angewandte Chemie.

[70]  R. Fletterick,et al.  Discovery of Small Molecule Inhibitors of the Interaction of the Thyroid Hormone Receptor with Transcriptional Coregulators* , 2005, Journal of Biological Chemistry.

[71]  A. G. Herreros,et al.  The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells , 2000, Nature Cell Biology.

[72]  Jared T. Shaw,et al.  Synthesis of diverse lactam carboxamides leading to the discovery of a new transcription-factor inhibitor. , 2007, Angewandte Chemie.

[73]  Bianca Sperl,et al.  Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. , 2006, Chemistry & biology.

[74]  Olov Sterner,et al.  Galiellalactone is a novel therapeutic candidate against hormone‐refractory prostate cancer expressing activated Stat3 , 2008, The Prostate.

[75]  V. Setola,et al.  Improvement of pharmacological properties of irreversible thyroid receptor coactivator binding inhibitors. , 2009, Journal of medicinal chemistry.

[76]  W. Guida,et al.  A small-molecule E2F inhibitor blocks growth in a melanoma culture model. , 2008, Cancer research.

[77]  Bulbul Pandit,et al.  Design, synthesis, and studies of small molecule STAT3 inhibitors. , 2008, Bioorganic & medicinal chemistry letters.

[78]  D. Boger,et al.  Disruption of the MYC transcriptional function by a small-molecule antagonist of MYC/MAX dimerization. , 2008, Oncology reports.