Novel PIKK inhibitor antibody-drug conjugates: Synthesis and anti-tumor activity

  • Bioorg Med Chem Lett. 2019 Apr 1;29(7):943-947. doi: 10.1016/j.bmcl.2019.01.009.
Dahui Zhou  1 ,  Jeffrey Casavant  2 ,  Edmund I Graziani  2 ,  Haiyin He  2 ,  Jeffrey Janso  2 ,  Frank Loganzo  3 ,  Sylvia Musto  3 ,  Nathan Tumey  2 ,  Christopher J O'Donnell  2 ,  Russell Dushin  2
Affiliations
  • 1. Oncology Medicinal Chemistry, Pfizer Worldwide Research and Development, 445 Eastern Point Road, Groton, CT 06340, United States. Electronic address: [email protected].
  • 2. Oncology Medicinal Chemistry, Pfizer Worldwide Research and Development, 445 Eastern Point Road, Groton, CT 06340, United States.
  • 3. Oncology Research East, Pfizer Worldwide Research and Development, 401 North Middletown Road, Pearl River, NY 10965, United States.
PMID: 30655215 DOI: 10.1016/j.bmcl.2019.01.009
Abstract

Novel neolymphostin-based antibody-drug conjugate (ADC) precursors were synthesized either through amide couplings between both cleavable and non-cleavable linkers and neolymphostin derivatives, or through Cu(I)-catalyzed acetylene-azide click cycloadditon between non-cleavable linkers and neolymphostin acetal derivatives. These precursors were site-specifically conjugated to cysteine mutant trastuzumab-A114C to provide neolymphostin-based ADCs. Preliminary in vitro data indicated that the corresponding ADCs were active against HER2-expressing tumor cell lines, thus providing a proof-of-concept for using neolymphostin as ADC-based Anticancer agents.

Keywords
ADC; Antitumor; HER2-expressing tumor cell lines; Neolymphostin; PIKK inhibitor; Trastuzumab conjugates.
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