2. Academic Validation
  3. Exploration of the carmaphycins as payloads in antibody drug conjugate anticancer agents

Exploration of the carmaphycins as payloads in antibody drug conjugate anticancer agents

  • Eur J Med Chem. 2019 Jan 1;161:416-432. doi: 10.1016/j.ejmech.2018.10.024.
Jehad Almaliti 1,  Bailey Miller 2,  Halina Pietraszkiewicz 3,  Evgenia Glukhov 4,  C Benjamin Naman 5,  Toni Kline 6,  Jeffrey Hanson 6,  Xiaofan Li 6,  Sihong Zhou 6,  Frederick A Valeriote 3,  William H Gerwick 7
Affiliations

Affiliations

  • 1 Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, 92093, United States; Department Pharmaceutical Sciences, College of Pharmacy, The University of Jordan, Amman, 11942, Jordan.
  • 2 Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, 92093, United States.
  • 3 Department of Internal Medicine, Division of Hematology and Oncology, Henry Ford Hospital, Detroit, MI, 48202, USA.
  • 4 Department Pharmaceutical Sciences, College of Pharmacy, The University of Jordan, Amman, 11942, Jordan.
  • 5 Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, 92093, United States; College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang, 315211, China.
  • 6 Sutro Biopharma, South San Francisco, CA, 94080, United States.
  • 7 Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, 92093, United States; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, 92093, United States. Electronic address: wgerwick@ucsd.edu.
PMID: 30384045 DOI: 10.1016/j.ejmech.2018.10.024
Abstract

Antibody-drug conjugates (ADCs) represent a new dimension of Anticancer chemotherapeutics, with warheads to date generally involving either antitubulin or DNA-directed agents to achieve low-to sub-nanomolar potency. However, other potent cytotoxins working by different pharmacological mechanisms are under investigation, such as α,β-epoxyketone based Proteasome inhibitors. These Proteasome active agents are an emerging class of Anticancer drug that possesses ultra-potent cytotoxicity to some Cancer cell lines. The carmaphycins are representatives of this latter class that we isolated and characterized from a marine cyanobacterium, and these as well as several synthetic analogues exhibit this level of potency. In the current work, we investigated the use of these highly potent cytotoxic compounds as warheads in the design of novel ADCs. We designed and synthesized a library of carmaphycin B analogues that contain amine handles, enabling their attachment to an antibody linker. The basicity of these incorporated amine handles was shown to strongly affect their cytotoxic properties. Linear amines resulted in the greatest reduction in cytotoxicity whereas less basic aromatic amines retained potent activity as demonstrated by a 4-sulfonylaniline derivative. These investigations resulted in identifying the P2 residue in the carmaphycins as the most suitable site for linker attachment point, and hence, we synthesized a highly potent analogue of carmaphycin B that contained a 4-sulfonylaniline handle as an attachment point for the linker antibody.

Keywords

4-Sulfonylaniline; Amine basicity optimization; Antibody-drug conjugate; Anticancer drugs; Carmaphycins; Proteasome inhibitors.

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