Optimization of a Novel DEL Hit That Binds in the Cbl-b SH2 Domain and Blocks Substrate Binding

IF 3.5 3区 医学 Q2 CHEMISTRY, MEDICINAL
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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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.

Abstract Image

Abstract Image

优化结合到 Cbl-b SH2 域并阻断底物结合的新型 DEL Hit
我们被抑制卡西塔斯 B 线淋巴瘤原癌基因-b(Cbl-b)的治疗潜力所吸引,Cbl-b 是一种 RING E3 连接酶,在调节 T 细胞的活化过程中发挥着关键作用。然而,由于只涉及蛋白质与蛋白质之间的相互作用,还不清楚用小分子抑制是否是一种可行的方法。在利用活化的 Cbl-b 筛选了一个 60 亿个 DNA 编码文库(DEL)后,我们确定化合物 1 为命中化合物,其顺式异构体(2)已通过生化和表面等离子体共振(SPR)测定得到证实。当我们获得了 2 与 Cbl-b 的共晶体结构后,我们对化合物的优化工作大大加快,该结构显示了在底物结合位点(即 Src 同源-2(SH2)结构域)的诱导结合。鉴于很少有报道称小分子抑制剂能与 SH2 结构域结合并阻断蛋白质与蛋白质之间的相互作用,这一点非常值得注意。通过结构和性质指导下的优化,最终得到了化合物 27,该化合物具有可测量的细胞活性,尽管只是在高浓度下。
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来源期刊
ACS Medicinal Chemistry Letters
ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-
CiteScore
7.30
自引率
2.40%
发文量
328
审稿时长
1 months
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.
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