|Title||Exploration of the carmaphycins as payloads in antibody drug conjugate anticancer agents|
|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Almaliti J., Miller B., Pietraszkiewicz H., Glukhov E., Naman C.B, Kline T., Hanson J., Li X.F, Zhou S.H, Valeriote F.A, Gerwick WH|
|Type of Article||Article|
|Keywords||4-Sulfonylaniline; Amine; Antibody-drug conjugate; Anticancer drugs; basicity optimization; bortezomib; Carmaphycins; cyanobacteria; design; future; generation; marine; natural-products; nonnatural amino-acids; peptide; Pharmacology & Pharmacy; proteasome inhibitors|
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 alpha,beta-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. (C) 2018 Elsevier Masson SAS. All rights reserved.