Bio

Bio


Gerald R. Crabtree lab member 2010-present (postdoctoral research).
Stuart L. Schreiber lab member 2004-2009 (Harvard University & Broad Institute, graduate research).
Richard B. Silverman lab member 2002-2004 (Northwestern University, undergraduate research).

Professional Education


  • Doctor of Philosophy, Harvard University (2009)

Stanford Advisors


Patents


  • Benjamin Stanton. "United StatesSONIC HEDGEHOG INHIBITORS", Harvard University

Publications

Journal Articles


  • Discovery of Small-Molecule Modulators of the Sonic Hedgehog Pathway JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Schaefer, G. I., Perez, J. R., Duvall, J. R., Stanton, B. Z., Shamji, A. F., Schreiber, S. L. 2013; 135 (26): 9675-9680

    Abstract

    The Hedgehog signaling pathway is involved in the development of multicellular organisms and, when deregulated, can contribute to certain cancers, among other diseases. The molecular characterization of the pathway, which has been enabled by small-molecule probes targeting its components, remains incomplete. Here, we report the discovery of two potent, small-molecule inhibitors of the Sonic Hedgehog (Shh) pathway, BRD50837 and BRD9526. Both compounds exhibit stereochemistry-based structure-activity relationships, a feature suggestive of a specific and selective interaction of the compounds with as-yet-unknown cellular target(s) and made possible by the strategy used to synthesize them as members of a stereochemically and skeletally diverse screening collection. The mechanism-of-action of these compounds in some ways shares similarities to that of cyclopamine, a commonly used pathway inhibitor. Yet, in other ways their mechanism-of-action is strikingly distinct. We hope that these novel compounds will be useful probes of this complex signaling pathway.

    View details for DOI 10.1021/ja400034k

    View details for Web of Science ID 000321541800028

    View details for PubMedID 23725514

  • Macrocyclic Hedgehog Pathway Inhibitors: Optimization of Cellular Activity and Mode of Action Studies. ACS medicinal chemistry letters Dockendorff, C., Nagiec, M. M., Weïwer, M., Buhrlage, S., Ting, A., Nag, P. P., Germain, A., Kim, H. J., Youngsaye, W., Scherer, C., Bennion, M., Xue, L., Stanton, B. Z., Lewis, T. A., Macpherson, L., Palmer, M., Foley, M. A., Perez, J. R., Schreiber, S. L. 2012; 3 (10): 808-813

    Abstract

    Macrocyclic Hedgehog (Hh) pathway inhibitors have been discovered with improved potency and maximal inhibition relative to the previously reported macrocycle robotnikinin. Analogues were prepared using a modular and efficient build-couple-pair (BCP) approach, with a ring-closing metathesis step to form the macrocyclic ring. Varying the position of the macrocycle nitrogen and oxygen atoms provided inhibitors with improved activity in cellular assays; the most potent analogue was 29 (BRD-6851), with an IC(50) of 0.4 μM against C3H10T1/2 cells undergoing Hh-induced activation, as measured by Gli1 transcription and alkaline phosphatase induction. Studies with Patched knockout (Ptch(-/-)) cells and competition studies with the Smoothened (Smo) agonists SAG and purmorphamine demonstrate that in contrast to robotnikinin, select analogues are Smo antagonists.

    View details for DOI 10.1021/ml300172p

    View details for PubMedID 23074541

  • Small-molecule modulators of the Sonic Hedgehog signaling pathway MOLECULAR BIOSYSTEMS Stanton, B. Z., Peng, L. F. 2010; 6 (1): 44-54

    Abstract

    Sonic hedgehog (Shh) is the most widely characterized of the three vertebrate Hedgehog homologs, and is essential for proper embryonic development. Shh binds to its receptor, Patched (Ptch1), resulting in the de-repression of Smoothened (Smo). This leads to the activation of Gli2, which regulates the transcription of target genes that include Gli1 and Ptch1. Several synthetic and naturally occurring small-molecule modulators of Smo have been discovered. Shh-signaling antagonists that bind to Smo include cyclopamine, SANT1, and Cur-61414. Shh signaling agonists that bind to Smo include the synthetic small molecules purmorphamine and SAG. Small molecules that inhibit Shh signaling downstream of Smo, GANT58 and GANT61 have also been reported. Robotnikinin inhibits the Shh pathway by directly targeting Shh. Although progress has been made in understanding and modulating Shh signaling, fundamental aspects of Shh signal transduction remain obscure, including the mechanism(s) whereby Ptch1 regulates Smo activity. Small-molecule modulators of Shh signaling provide a means to regulate the activity of a pathway implicated in medulloblastoma, basal cell carcinoma (BCC), pancreatic cancer, prostate cancer and developmental disorders. Several Shh inhibitors have not succeeded in the clinic for unknown reasons, but clinical trials in BCC and pancreatic cancer with the promising Smo antagonists GDC-0449 and IPI-926 are currently underway.

    View details for DOI 10.1039/b910196a

    View details for Web of Science ID 000272875200005

    View details for PubMedID 20024066

  • Syntheses of aminoalcohol-derived macrocycles leading to a small-molecule binder to and inhibitor of Sonic Hedgehog BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Peng, L. F., Stanton, B. Z., Maloof, N., Wang, X., Schreiber, S. L. 2009; 19 (22): 6319-6325

    Abstract

    We report the synthesis and biological activity of a library of aminoalcohol-derived macrocycles from which robotnikinin, a binder to and inhibitor of Sonic Hedgehog, was derived. Using an asymmetric alkylation to set a key stereocenter and an RCM reaction to close the macrocycle, we were able to synthesize compounds for testing. High-throughput screening via small-molecule microarray (SMM) technology led to the discovery of a compound capable of binding ShhN. Follow-up chemistry led to a library of macrocycles with enhanced biological activity relative to the original hit compounds. Differences in ring size and stereochemistry, leading to alterations in the mode of binding, may account for differences in the degree of biological activity. These compounds are the first ones reported that inhibit Shh signaling at the ShhN level.

    View details for DOI 10.1016/j.bmcl.2009.09.089

    View details for Web of Science ID 000271029600014

    View details for PubMedID 19819139

  • A small molecule that binds Hedgehog and blocks its signaling in human cells NATURE CHEMICAL BIOLOGY Stanton, B. Z., Peng, L. F., Maloof, N., Nakai, K., Wang, X., Duffner, J. L., Taveras, K. M., Hyman, J. M., Lee, S. W., Koehler, A. N., Chen, J. K., Fox, J. L., Mandinova, A., Schreiber, S. L. 2009; 5 (3): 154-156

    Abstract

    Small-molecule inhibition of extracellular proteins that activate membrane receptors has proven to be extremely challenging. Diversity-oriented synthesis and small-molecule microarrays enabled the discovery of robotnikinin, a small molecule that binds the extracellular Sonic hedgehog (Shh) protein and blocks Shh signaling in cell lines, human primary keratinocytes and a synthetic model of human skin. Shh pathway activity is rescued by small-molecule agonists of Smoothened, which functions immediately downstream of the Shh receptor Patched.

    View details for DOI 10.1038/nchembio.142

    View details for Web of Science ID 000263556100012

    View details for PubMedID 19151731

  • Minimal pharmacophoric elements and fragment hopping, an approach directed at molecular diversity and isozyme selectivity. Design of selective neuronal nitric oxide synthase inhibitors JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Ji, H., Stanton, B. Z., Igarashi, J., Li, H., Martasek, P., Roman, L. J., Poulos, T. L., Silverman, R. B. 2008; 130 (12): 3900-3914

    Abstract

    Fragment hopping, a new fragment-based approach for de novo inhibitor design focusing on ligand diversity and isozyme selectivity, is described. The core of this approach is the derivation of the minimal pharmacophoric element for each pharmacophore. Sites for both ligand binding and isozyme selectivity are considered in deriving the minimal pharmacophoric elements. Five general-purpose libraries are established: the basic fragment library, the bioisostere library, the rules for metabolic stability, the toxicophore library, and the side chain library. These libraries are employed to generate focused fragment libraries to match the minimal pharmacophoric elements for each pharmacophore and then to link the fragment to the desired molecule. This method was successfully applied to neuronal nitric oxide synthase (nNOS), which is implicated in stroke and neurodegenerative diseases. Starting with the nitroarginine-containing dipeptide inhibitors we developed previously, a small organic molecule with a totally different chemical structure was designed, which showed nanomolar nNOS inhibitory potency and more than 1000-fold nNOS selectivity. The crystallographic analysis confirms that the small organic molecule with a constrained conformation can exactly mimic the mode of action of the dipeptide nNOS inhibitors. Therefore, a new peptidomimetic strategy, referred to as fragment hopping, which creates small organic molecules that mimic the biological function of peptides by a pharmacophore-driven strategy for fragment-based de novo design, has been established as a new type of fragment-based inhibitor design. As an open system, the newly established approach efficiently incorporates the concept of early "ADME/Tox" considerations and provides a basic platform for medicinal chemistry-driven efforts.

    View details for DOI 10.1021/ja0772041

    View details for Web of Science ID 000254173600049

    View details for PubMedID 18321097

  • Structure-activity relationship study of antimalarial indolo [2,1-b]quinazoline-6,12-diones (tryptanthrins). Three dimensional pharmacophore modeling and identification of new antimalarial candidates EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY Bhattacharjee, A. K., Hartell, M. G., Nichols, D. A., Hicks, R. P., Stanton, B., van Hamont, J. E., Milhous, W. K. 2004; 39 (1): 59-67

    Abstract

    A widely applicable three-dimensional QSAR pharmacophore model for antimalarial activity was developed from a set of 17 substituted antimalarial indolo[2,1-b]quinazoline-6,12-diones (tryptanthrins) that exhibited remarkable in vitro activity (below 100 ng/mL) against sensitive and multidrug-resistant Plasmodium falciparum malaria. The pharmacophore, which contains two hydrogen bond acceptors (lipid) and two hydrophobic (aromatic) features, was found to map well onto many well-known antimalarial drug classes including quinolines, chalcones, rhodamine dyes, Pfmrk cyclin dependent kinase inhibitors, malarial FabH inhibitors, and plasmepsin inhibitors. The phamacophore allowed searches for new antimalarial candidates from multiconformer 3D databases and enabled custom designed synthesis of new potent analogues.

    View details for DOI 10.1016/j.ejmech.2003.10.004

    View details for Web of Science ID 000220506800006

    View details for PubMedID 14987834

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