Honors & Awards


  • Alex's Lemonade Stand Foundation Young Investigator Grant, ALSF (2015-2017)
  • Stanford Dean's Postdoctoral Fellowship, Stanford University (2014-2015)

Professional Education


  • Doctor of Philosophy, University of Southern California, Pharmaceutical Sciences (Olenyuk Lab) (2012)
  • Graduate Student, University of Arizona (2005-2010), Chemistry and Biochemistry (Olenyuk Lab)
  • Master of Science, Panjab University (2004)

Lab Affiliations


All Publications


  • Chromatin-remodeling complex SWI/SNF controls multidrug resistance by transcriptionally regulating the drug efflux pump ABCB1. Cancer research Dubey, R., Lebensohn, A., Bahrami-Nejad, Z., Marceau, C., Champion, M., Gevaert, O., Sikic, B. I., Carette, J. E., Rohatgi, R. 2016

    Abstract

    Anthracyclines are among the most effective yet most toxic drugs used in the oncology clinic. The nucleosome-remodeling SWI/SNF complex, a potent tumor suppressor, is thought to promote sensitivity to anthracyclines by recruiting topoisomerase IIa (TOP2A) to DNA and increasing double-strand breaks. In this study, we discovered a novel mechanism through which SWI/SNF influences resistance to the widely used anthracycline doxorubicin (Dox), based on the use of a forward genetic screen in haploid human cells followed by a rigorous single and double-mutant epistasis analysis using CRISPR/Cas9-mediated engineering. Dox resistance conferred by loss of the SMARCB1 subunit of the SWI/SNF complex was caused by transcriptional upregulation of a single gene, encoding the multi-drug resistance pump ABCB1. Remarkably, both ABCB1 upregulation and Dox resistance caused by SMARCB1 loss was dependent on the function of SMARCA4, a catalytic subunit of the SWI/SNF complex. We propose that residual SWI/SNF complexes lacking SMARCB1 are vital determinants of drug sensitivity, not just to TOP2A-targeted agents, but to the much broader range of cancer drugs effluxed by ABCB1.

    View details for DOI 10.1158/0008-5472.CAN-16-0716

    View details for PubMedID 27503929

  • Small-molecule-directed, efficient generation of retinal pigment epithelium from human pluripotent stem cells PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Maruotti, J., Sripathi, S. R., Bharti, K., Fuller, J., Wahlin, K. J., Ranganathan, V., Sluch, V. M., Berlinicke, C. A., Davis, J., Kim, C., Zhao, L., Wan, J., Qian, J., Corneo, B., Temple, S., Dubey, R., Olenyuk, B. Z., Bhutto, I., Lutty, G. A., Zack, D. J. 2015; 112 (35): 10950-10955

    Abstract

    Age-related macular degeneration (AMD) is associated with dysfunction and death of retinal pigment epithelial (RPE) cells. Cell-based approaches using RPE-like cells derived from human pluripotent stem cells (hPSCs) are being developed for AMD treatment. However, most efficient RPE differentiation protocols rely on complex, stepwise treatments and addition of growth factors, whereas small-molecule-only approaches developed to date display reduced yields. To identify new compounds that promote RPE differentiation, we developed and performed a high-throughput quantitative PCR screen complemented by a novel orthogonal human induced pluripotent stem cell (hiPSC)-based RPE reporter assay. Chetomin, an inhibitor of hypoxia-inducible factors, was found to strongly increase RPE differentiation; combination with nicotinamide resulted in conversion of over one-half of the differentiating cells into RPE. Single passage of the whole culture yielded a highly pure hPSC-RPE cell population that displayed many of the morphological, molecular, and functional characteristics of native RPE.

    View details for DOI 10.1073/pnas.1422818112

    View details for Web of Science ID 000360383200049

    View details for PubMedID 26269569

  • Tumor Targeting, Trifunctional Dendritic Wedge BIOCONJUGATE CHEMISTRY Dubey, R., Kushal, S., Mollard, A., Vojtovich, L., Oh, P., Levin, M. D., Schnitzer, J. E., Zharov, I., Olenyuk, B. Z. 2015; 26 (1): 78-89

    Abstract

    We report in vitro and in vivo evaluation of a newly designed trifunctional theranostic agent for targeting solid tumors. This agent combines a dendritic wedge with high boron content for boron neutron capture therapy or boron MRI, a monomethine cyanine dye for visible-light fluorescent imaging, and an integrin ligand for efficient tumor targeting. We report photophysical properties of the new agent, its cellular uptake and in vitro targeting properties. Using live animal imaging and intravital microscopy (IVM) techniques, we observed a rapid accumulation of the agent and its retention for a prolonged period of time (up to 7 days) in fully established animal models of human melanoma and murine mammary adenocarcinoma. This macromolecular theranostic agent can be used for targeted delivery of high boron load into solid tumors for future applications in boron neutron capture therapy.

    View details for DOI 10.1021/bc500436b

    View details for Web of Science ID 000348483200009

    View details for PubMedID 25350602

  • Protein domain mimetics as in vivo modulators of hypoxia-inducible factor signaling PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Kushal, S., Lao, B. B., Henchey, L. K., Dubey, R., Mesallati, H., Traaseth, N. J., Olenyuk, B. Z., Arora, P. S. 2013; 110 (39): 15602-15607

    Abstract

    Selective blockade of gene expression by designed small molecules is a fundamental challenge at the interface of chemistry, biology, and medicine. Transcription factors have been among the most elusive targets in genetics and drug discovery, but the fields of chemical biology and genetics have evolved to a point where this task can be addressed. Herein we report the design, synthesis, and in vivo efficacy evaluation of a protein domain mimetic targeting the interaction of the p300/CBP coactivator with the transcription factor hypoxia-inducible factor-1α. Our results indicate that disrupting this interaction results in a rapid down-regulation of hypoxia-inducible genes critical for cancer progression. The observed effects were compound-specific and dose-dependent. Gene expression profiling with oligonucleotide microarrays revealed effective inhibition of hypoxia-inducible genes with relatively minimal perturbation of nontargeted signaling pathways. We observed remarkable efficacy of the compound HBS 1 in suppressing tumor growth in the fully established murine xenograft models of renal cell carcinoma of the clear cell type. Our results suggest that rationally designed synthetic mimics of protein subdomains that target the transcription factor-coactivator interfaces represent a unique approach for in vivo modulation of oncogenic signaling and arresting tumor growth.

    View details for DOI 10.1073/pnas.1312473110

    View details for Web of Science ID 000324765100031

    View details for PubMedID 24019500

  • Suppression of Tumor Growth by Designed Dimeric Epidithiodiketopiperazine Targeting Hypoxia-Inducible Transcription Factor Complex JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Dubey, R., Levin, M. D., Szabo, L. Z., Laszlo, C. F., Kushal, S., Singh, J. B., Oh, P., Schnitzer, J. E., Olenyuk, B. Z. 2013; 135 (11): 4537-4549

    Abstract

    Hypoxia is a hallmark of solid tumors, is associated with local invasion, metastatic spread, resistance to chemo- and radiotherapy, and is an independent, negative prognostic factor for a diverse range of malignant neoplasms. The cellular response to hypoxia is primarily mediated by a family of transcription factors, among which hypoxia-inducible factor 1 (HIF1) plays a major role. Under normoxia, the oxygen-sensitive α subunit of HIF1 is rapidly and constitutively degraded but is stabilized and accumulates under hypoxia. Upon nuclear translocation, HIF1 controls the expression of over 100 genes involved in angiogenesis, altered energy metabolism, antiapoptotic, and pro-proliferative mechanisms that promote tumor growth. A designed transcriptional antagonist, dimeric epidithiodiketopiperazine (ETP 2), selectively disrupts the interaction of HIF1α with p300/CBP coactivators and downregulates the expression of hypoxia-inducible genes. ETP 2 was synthesized via a novel homo-oxidative coupling of the aliphatic primary carbons of the dithioacetal precursor. It effectively inhibits HIF1-induced activation of VEGFA, LOX, Glut1, and c-Met genes in a panel of cell lines representing breast and lung cancers. We observed an outstanding antitumor efficacy of both (±)-ETP 2 and meso-ETP 2 in a fully established breast carcinoma model by intravital microscopy. Treatment with either form of ETP 2 (1 mg/kg) resulted in a rapid regression of tumor growth that lasted for up to 14 days. These results suggest that inhibition of HIF1 transcriptional activity by designed dimeric ETPs could offer an innovative approach to cancer therapy with the potential to overcome hypoxia-induced tumor growth and resistance.

    View details for DOI 10.1021/ja400805b

    View details for Web of Science ID 000316774100050

    View details for PubMedID 23448368

  • Inhibition of Hypoxia Inducible Factor 1-Transcription Coactivator Interaction by a Hydrogen Bond Surrogate alpha-Helix JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Henchey, L. K., Kushal, S., Dubey, R., Chapman, R. N., Olenyuk, B. Z., Arora, P. S. 2010; 132 (3): 941-?

    Abstract

    Designed ligands that inhibit hypoxia-inducible gene expression could offer new tools for genomic research and, potentially, drug discovery efforts for the treatment of neovascularization in cancers. We report a stabilized alpha-helix designed to target the binding interface between the C-terminal transactivation domain (C-TAD) of hypoxia-inducible factor 1alpha (HIF-1alpha) and cysteine-histidine rich region (CH1) of transcriptional coactivator CBP/p300. The synthetic helix disrupts the structure and function of this complex, resulting in a rapid downregulation of two hypoxia-inducible genes (VEGF and GLUT1) in cell culture.

    View details for DOI 10.1021/ja9082864

    View details for Web of Science ID 000275084700018

    View details for PubMedID 20041650

  • Direct organocatalytic coupling of carboxylated piperazine-2,5-diones with indoles through conjugate addition of carbon nucleophiles to indolenine intermediates. Tetrahedron letters Dubey, R., Olenyuk, B. 2010; 51 (4): 609-612

    Abstract

    The indole-diketopiperazine bridge is an important structural feature of many bispyrrolidinoindoline and epipolythiodiketopiperazine fungal metabolites. Organocatalytic conjugate addition of diketopiperazines to indoles was achieved in good to excellent yields through electrophilic indolenine intermediates generated under mild conditions. Screening of catalysts and solvents at different temperatures was performed in order to achieve high product yields.

    View details for DOI 10.1016/j.tetlet.2009.11.068

    View details for PubMedID 20161551

  • Direct Inhibition of Hypoxia-Inducible Transcription Factor Complex with Designed Dimeric Epidithiodiketopiperazine JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Block, K. M., Wang, H., Szabo, L. Z., Polaske, N. W., Henchey, L. K., Dubey, R., Kushal, S., Laszlo, C. F., Makhoul, J., Song, Z., Meuillet, E. J., Olenyuk, B. Z. 2009; 131 (50): 18078-18088

    Abstract

    Selective blockade of hypoxia-inducible gene expression by designed small molecules would prove valuable in suppressing tumor angiogenesis, metastasis and altered energy metabolism. We report the design, synthesis, and biological evaluation of a dimeric epidithiodiketopiperazine (ETP) small molecule transcriptional antagonist targeting the interaction of the p300/CBP coactivator with the transcription factor HIF-1alpha. Our results indicate that disrupting this interaction results in rapid downregulation of hypoxia-inducible genes critical for cancer progression. The observed effects are compound-specific and dose-dependent. Controlling gene expression with designed small molecules targeting the transcription factor-coactivator interface may represent a new approach for arresting tumor growth.

    View details for DOI 10.1021/ja807601b

    View details for Web of Science ID 000273615400030

    View details for PubMedID 20000859

  • Enantioselective organocatalytic alpha-sulfenylation of substituted diketopiperazines. Tetrahedron, asymmetry Polaske, N. W., Dubey, R., Nichol, G. S., Olenyuk, B. 2009; 20 (23): 2742-2750

    Abstract

    The asymmetric organocatalytic alpha-sulfenylation of substituted piperazine-2,5-diones is reported, with cinchona alkaloids as chiral Lewis bases and electrophilic sulfur transfer reagents. Catalyst loadings, the type of sulfur transfer reagent, temperature and solvent were investigated in order to optimize the reaction conditions. The effects of ring substitution and the type of catalyst on the yield and enantioselectivity of the reaction are reported.

    View details for DOI 10.1016/j.tetasy.2009.10.037

    View details for PubMedID 20161615

  • Efficient Organocatalytic alpha-Sulfenylation of Substituted Piperazine-2,5-diones. Tetrahedron letters Dubey, R., Polaske, N. W., Nichol, G. S., Olenyuk, B. 2009; 50 (30): 4310-4313

    Abstract

    Organocatalytic alpha-sulfenylation of substituted piperazine-2,5-diones is reported through the use of cinchona alkaloids as Lewis bases and electrophilic sulfur transfer reagents. 1-Phenylsulfanyl[1,2,4]triazole, a novel sulfur transfer reagent, gave excellent product yields with a number of substituted piperazine-2,5-diones under mild conditions. Catalyst loading, stoichiometry of sulfur electrophile, temperature and solvent were optimized to achieve high product yields.

    View details for DOI 10.1016/j.tetlet.2009.05.031

    View details for PubMedID 20161311