Optimization of 2-(3-(3-Carbamoylpiperidin-1-yl)phenoxy)acetic Acid Derivatives as Potent and Selective Inhibitors of the β-Catenin/BCL9 Protein-Protein Interaction
The development of selective inhibitors targeting the β-catenin/BCL9 protein-protein interaction (PPI) has emerged as a strategic approach to suppress oncogenic Wnt signaling in cancer. This study describes the comprehensive medicinal chemistry optimization of a hit compound series derived from 2-(3-(3-carbamoylpiperidin-1-yl)phenoxy)acetic acid, leading to the identification of highly potent and selective small-molecule disruptors.
Initial screening revealed that the parent compound exhibited moderate inhibitory activity with a Ki value of 11 μM in AlphaScreen assays. Structural modifications were guided by the need to improve metabolic stability and synthetic accessibility. Replacement of the metabolically labile carbamate group with an amide linkage yielded compound 2, which showed reduced potency but enhanced chemical robustness.6902-77-8 custom synthesis Subsequent SAR exploration focused on the amide substituent and the piperidine ring system. Introduction of alkyl groups at the amide nitrogen progressively improved activity, culminating in compound 7, which displayed a Ki of 36 μM.
Further enhancement was achieved through strategic incorporation of heterocyclic moieties at the isopropyl position. Notably, thiophene-containing derivatives demonstrated superior potency, with compound 12 exhibiting a Ki of 13 μM—comparable to the original hit. However, compound 12 lacked cellular activity due to its carboxylic acid functionality, which compromises membrane permeability.122111-03-9 site To address this limitation, a bioisosteric replacement strategy was employed using N-acyl sulfonamide groups, known for their ability to enhance cell penetration and metabolic stability.
This led to the design of a new series of compounds featuring various substituted benzenesulfonamides. Compound 21, bearing a phenylsulfonamide moiety, showed a Ki of 6.4 μM, representing a twofold improvement over compound 12. Further optimization introduced polar substituents such as methoxy and cyano groups on the phenyl ring. The resulting compounds 22 and 26 emerged as the most potent inhibitors, with Ki values of 4.PMID:30252390 1 μM and 3.9 μM, respectively.
Chiral separation of these enantiomers revealed that the S-isomer (compound 30) consistently outperformed its R-counterpart (compound 29), indicating stereospecific binding within the target interface. Compound 30 was selected for detailed biological evaluation due to its exceptional potency and favorable physicochemical properties.
In functional assays, compound 30 effectively inhibited Wnt/β-catenin signaling in multiple cancer cell lines, including colorectal and breast cancer models, with IC50 values ranging from 14 to 30 μM. Importantly, it showed minimal cytotoxicity toward normal epithelial cells, demonstrating a >5-fold selectivity window. Mechanistic studies confirmed its ability to selectively disrupt the β-catenin/BCL9 complex without interfering with the β-catenin/E-cadherin interaction, supporting its specificity.
These findings establish compound 30 as a highly potent, selective, and cell-active inhibitor of the β-catenin/BCL9 PPI. Its novel scaffold and favorable profile make it a promising lead for the development of targeted therapies against Wnt-driven cancers.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com