2. Academic Validation
  3. Evaluation of PNU-159682 antibody drug conjugates (ADCs)

Evaluation of PNU-159682 antibody drug conjugates (ADCs)

  • Bioorg Med Chem Lett. 2020 Dec 15;30(24):127640. doi: 10.1016/j.bmcl.2020.127640.
Dane Holte 1,  Joseph P Lyssikatos 2,  Amanda M Valdiosera 3,  Zachary Swinney 4,  Vikram Sisodiya 5,  Joseph Sandoval 6,  Christina Lee 7,  Monette A Aujay 2,  Robert B Tchelepi 8,  Omar M Hamdy 9,  Christine Gu 10,  Baiwei Lin 11,  Hetal Sarvaiya 7,  Marybeth A Pysz 7,  Amy Laysang 7,  Samuel Williams 12,  Dong Jun Lee 13,  Magda K Holda 14,  James W Purcell 7,  Julia Gavrilyuk 7
Affiliations

Affiliations

  • 1 AbbVie Chemical Development & Manufacturing, 995 East Arques Avenue, Sunnyvale, CA 94085, USA. Electronic address: dane.holte@abbvie.com.
  • 2 Enliven Therapeutics, 6200 Lookout Road, First Floor, Boulder, CO 80301, USA.
  • 3 Parvus Therapeutics, 800 Dubuque Avenue, South San Francisco, CA 94080, USA.
  • 4 Mantra Bio, 455 Mission Bay Boulevard, South San Francisco, CA 94158, USA.
  • 5 Denali Therapeutics, 161 Oyster Point Bloulevard, South San Francisco, CA 94080, USA.
  • 6 Fate Therapeutics, 3535 General Atomics Court, Suite 200, San Diego 92121, USA.
  • 7 AbbVie Research & Development, 400 East Jamie Court, South San Francisco, CA 94080, USA.
  • 8 Bolt Biotherapeutics, 640 Galveston Drive, Redwood City, CA 94063, USA.
  • 9 Applied Molecular Transport, 1 Tower Place, Suite 850, South San Francisco, CA 94080, USA.
  • 10 AbbVie Research & Development, 400 East Jamie Court, South San Francisco, CA 94080, USA; AbbVie Research & Development, 995 East Arques Avenue, Sunnyvale, CA 94085, USA.
  • 11 Maze Therapeutics, 131 Oyster Point Blvd, Suite 200, South San Francisco, CA 94080, USA.
  • 12 ArsenalBio, Inc. 2 Tower Place, South San Francisco, CA 94080, USA.
  • 13 AbbVie Research & Development, 995 East Arques Avenue, Sunnyvale, CA 94085, USA.
  • 14 AbbVie Research & Development, 1500 Seaport Blvd, Redwood City, CA 94063, USA.
PMID: 33127540 DOI: 10.1016/j.bmcl.2020.127640
Abstract

PNU-159682 is a highly potent secondary metabolite of nemorubicin belonging to the anthracycline class of Natural Products. Due to its extremely high potency and only partially understood mechanism of action, it was deemed an interesting starting point for the development of a new suite of linker drugs for antibody drug conjugates (ADCs). Structure activity relationships were explored on the small molecule which led to six linker drugs being developed for conjugation to Antibodies. Herein we describe the synthesis of novel PNU-159682 derivatives and the subsequent linker drugs as well as the corresponding biological evaluations of the small molecules and ADCs.

Keywords

Antibody drug conjugate; Doxorubicin; Nemorubicin; PNU-159682.

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