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Discovery and Development of RRx-001, a Novel Nitric Oxide and ROS Mediated Epigenetic Modulator

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Nitric Oxide and Cancer: Pathogenesis and Therapy

Abstract

Methods to find compounds that interact favorably with anti-cancer biological targets typically start from a limited set of structural types and focus on target-based approaches resulting in limited breakthroughs, mostly incremental improvements, and many structurally similar compounds that fall into ‘me too’ or ‘me better’ categories. Due to the very low success rate for drug development in oncology, different, ‘non-me too’ approaches that utilize novel chemotypes together with phenotypic discovery approaches are required to provide truly novel treatments. The defense and aerospace industry offers a huge resource of largely untapped chemical diversity that lends itself to a phenotypic approach to drug discovery. Herein we describe a novel program focused on discovering drug candidates from energetic materials that arose from a unique partnership between a defense contractor specializing in the research and utilization of energetic materials and an academic institution, under the umbrella of a start-up and with an innovative funding and organizational structure. We describe the most advanced compound, RRx-001, the first of a new class of NO-mediated epigenetic anticancer agents that bind hemoglobin and drive RBC-mediated redox reactions under hypoxia.

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Abbreviations

ABAZ:

N-bromoacetylazetidine

ADNAZ:

N-acetyl-3,3-dinitroazetidine

BSO:

Buthionine sulphoximine

CDDP:

Cisplatin

CEA:

carcinoembryonic antigen

CMC:

Chemistry, Manufacturing and Controls

CMO:

Contract Manufacturing Organization

CPT:

Cold Pressor Test

DLT:

Dose Limiting Toxicity

DNMT:

DNA methyltransferase

FOLFIRI:

Chemotherapy regimen for colorectal cancer: Folinic acid/Fluorouracil/irinotecan

GMP:

Good Manufacturing practice

HDAC:

Histoine deacetylases

HMNAZ:

1-tert-butyl-3- hydroxymethyl-3-nitroazetidine

IP:

Intraperitoneal route of administration

IV:

Intravenous route of administration

MTase:

Methyl transferases

MTD:

Maximum Tolerated Dose

NAC:

N-acetyl Cysteine

NO:

Nitric Oxide

PO:

Oral route of administration

QD:

Once daily

RBC:

Red Blood Cell

RNS:

Reactive Nitrogen Species

RONS:

Reactive Oxygen and Nitrogen Species

ROS:

Reactive Oxygen Species

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Acknowledgements

The authors greatly acknowledge the scientific foresight and ingenuity of the late Dr. Bednarski who was responsible for the genesis of RadioRx. We also gratefully acknowledge Dr. Arnold Oronsky and InterWest Partners for their willingness and courage to go out on a financial limb and fund an untested vision in the face of naysayers and sure criticism with novel, ‘non-me too’ materials as drug candidates. We also would like to acknowledge collaboration with Drs. R Wardle and L Cannizzo at ATK Aerospace Systems (ATK Thiokol) on the discovery of RRx-001. RadioRx also thank Dr. Tony Reid, our stalwart Principal Investigator as well as Drs. D Peehl, M Taylor, B Fitch, C Scribner, P Cabrales, F Kuypers and Mr. L Micheals for their invaluable contributions without which RRx-001 would not be where it is today.

Conflict Statement

All authors have ownership interest in RadioRx, Inc. (including patents and stock option). SJ Knox and M Bednarski are founders of RadioRx, Inc.

Author information

Authors and Affiliations

  1. EpicentRx, Inc, 800 W El Camino Real, Suite 180, 94040, Mountain View, CA, USA

    Jan Scicinski PhD, Bryan Oronsky & Gary R. Fanger

  2. Department of Radiation Oncology, Stanford University Medical Center, 94305, Stanford, CA, USA

    Shoucheng Ning & Susan J. Knox

  3. Department of Radiology, Stanford University Medical Center, 94305, Stanford, CA, USA

    Mark Bednarski

Authors
  1. Jan Scicinski PhD
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  2. Bryan Oronsky
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  3. Shoucheng Ning
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  4. Gary R. Fanger
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  5. Susan J. Knox
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  6. Mark Bednarski
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Corresponding author

Correspondence to Jan Scicinski PhD .

Editor information

Editors and Affiliations

  1. Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California of Los Angeles, Los Angeles, California, USA

    Benjamin Bonavida

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Scicinski, J., Oronsky, B., Ning, S., Fanger, G., Knox, S., Bednarski, M. (2015). Discovery and Development of RRx-001, a Novel Nitric Oxide and ROS Mediated Epigenetic Modulator. In: Bonavida, B. (eds) Nitric Oxide and Cancer: Pathogenesis and Therapy. Springer, Cham. https://doi.org/10.1007/978-3-319-13611-0_16

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