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. Epub 2020 Oct 28.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Doxorubicin / analogs & derivatives*
  • Doxorubicin / chemical synthesis
  • Doxorubicin / chemistry
  • Doxorubicin / pharmacology
  • Humans
  • Immunoconjugates / chemistry*
  • Immunoconjugates / pharmacology*
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasms / drug therapy

Substances

  • 3'-deamino-3'',4'-anhydro-(2''-methoxy-3''-oxy-4''-morpholinyl)doxorubicin
  • Antineoplastic Agents
  • Immunoconjugates
  • nemorubicin
  • Doxorubicin