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

• DOI: 10.1016/j.ejmech.2018.10.024
• Publication Date: 2018-10-15T16:37:39Z
• Authors: Jehad Almaliti; Bailey Miller; Halina Pietraszki...; Evgenia Glukhov; C. Benjamin Naman; Toni Kline; Jeffrey Hanson; Xiaofan Li; Sihong Zhou; Frederick A. Vale...; William H. Gerwick
• Keywords: 0301 basic medicine; Proteasome Endopeptidase Complex; Cell Survival; Medicinal & Biomolecular Chemistry; Carmaphycins; Organic chemistry; Antineoplastic Agents; Proteasome inhibitors; Drug Screening Assays; Anticancer drugs; Antibodies; Cell Line; Dose-Response Relationship; Medicinal and Biomolecular Chemistry; Structure-Activity Relationship; 03 medical and health sciences; Rare Diseases; Cell Line, Tumor; Monoclonal; Medicinal and biomolecular chemistry; Humans; Amines; Antibody-drug conjugate; Cancer; Cell Proliferation; 0303 health sciences; Tumor; Aniline Compounds; Dose-Response Relationship, Drug; Molecular Structure; Organic Chemistry; Antibodies, Monoclonal; Antitumor; Pharmacology and Pharmaceutical Sciences; 3. Good health; Orphan Drug; Pharmacology and pharmaceutical sciences; 5.1 Pharmaceuticals; Chemical Sciences; Amine basicity optimization; Development of treatments and therapeutic interventions; Drug; Drug Screening Assays, Antitumor; Oligopeptides; Proteasome Inhibitors; Biotechnology; 4-Sulfonylaniline

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.