1148157-29-2Relevant articles and documents
Systematic Analyses of Substrate Preferences of 20S Proteasomes Using Peptidic Epoxyketone Inhibitors
Huber, Eva M.,De Bruin, Gerjan,Heinemeyer, Wolfgang,Soriano, Guillem Paniagua,Overkleeft, Herman S.,Groll, Michael
, p. 7835 - 7842 (2015)
Cleavage analyses of 20S proteasomes with natural or synthetic substrates allowed to infer the substrate specificities of the active sites and paved the way for the rational design of high-affinity proteasome inhibitors. However, details of cleavage prefe
Exploration of the carmaphycins as payloads in antibody drug conjugate anticancer agents
Almaliti, Jehad,Miller, Bailey,Pietraszkiewicz, Halina,Glukhov, Evgenia,Naman, C. Benjamin,Kline, Toni,Hanson, Jeffrey,Li, Xiaofan,Zhou, Sihong,Valeriote, Frederick A.,Gerwick, William H.
, p. 416 - 432 (2018/10/31)
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.
Fluorinated epoxyketone-based compounds and uses thereof as proteasome inhibitors
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, (2016/09/28)
The present application relates to novel fluorinated epoxyketone-based compounds, compositions comprising these compounds and their use, in particular for the treatment of diseases, disorders or conditions mediated by proteasome inhibition, in particular, the present application includes compounds of Formula I, and compositions and uses thereof.