Jun Liang*, Michael J. Lambrecht, Teresita L. Arenzana, Samuel Aubert-Nicol, Linda Bao, Fabio Broccatelli, Jianping Cai, Celine Eidenschenk, Christine Everett, Thomas Garner, Felix Gruber, Pouyan Haghshenas, Malcolm P. Huestis, Peter L. Hsu, Ponien Kou, Araz Jakalian, Robin Larouche-Gauthier, Jean-Philippe Leclerc, Dennis H. Leung, Aaron Martin, Jeremy Murray, Madeleine Prangley, Sascha Rutz, Satoko Kakiuchi-Kiyota, Alexander Lee Satz, Nicholas J. Skelton, Micah Steffek, Daniel Stoffler, Jawahar Sudhamsu, Sophia Tan, Jian Wang, Shouliang Wang, Qiuyue Wang, Timothy J. Wendorff, Moreno Wichert, Arun Yadav, Christine Yu and Xiaojing Wang,
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引用次数: 0
Abstract
We were attracted to the therapeutic potential of inhibiting Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b), a RING E3 ligase that plays a critical role in regulating the activation of T cells. However, given that only protein–protein interactions were involved, it was unclear whether inhibition by a small molecule would be a viable approach. After screening an ∼6 billion member DNA-encoded library (DEL) using activated Cbl-b, we identified compound 1 as a hit for which the cis-isomer (2) was confirmed by biochemical and surface plasmon resonance (SPR) assays. Our hit optimization effort was greatly accelerated when we obtained a cocrystal structure of 2 with Cbl-b, which demonstrated induced binding at the substrate binding site, namely, the Src homology-2 (SH2) domain. This was quite noteworthy given that there are few reports of small molecule inhibitors that bind to SH2 domains and block protein–protein interactions. Structure- and property-guided optimization led to compound 27, which demonstrated measurable cell activity, albeit only at high concentrations.
期刊介绍:
ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to:
Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics)
Biological characterization of new molecular entities in the context of drug discovery
Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc.
Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry
Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources
Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response
Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic
Mechanistic drug metabolism and regulation of metabolic enzyme gene expression
Chemistry patents relevant to the medicinal chemistry field.