US20260053931
2026-02-26
Human necessities
A61K47/545
The application introduces novel compounds designed to degrade Mdm2, a protein involved in the regulation of the tumor suppressor p53. These compounds are presented in various formulas and their analogs, along with pharmaceutical compositions suitable for cancer treatment. The compounds aim to target cancers with different p53 statuses, including wild-type, mutated, inactivated, and null p53 variants.
Mdm2 is an E3 ubiquitin ligase that plays a critical role in maintaining low levels of p53 under non-stress conditions by promoting its degradation. The overproduction of Mdm2 is common in several human cancers, making it a target for drug discovery. Existing Mdm2 inhibitors have shown efficacy but are limited by toxic side effects and resistance issues due to increased Mdm2 levels and p53 mutations.
The disclosed compounds operate as Mdm2 targeting PROTACs (Proteolysis Targeting Chimeras), which are designed to degrade Mdm2 efficiently. These compounds consist of three main components: an Mdm2 inhibitor, a ubiquitin ligase ligand, and a linker group that forms covalent bonds with both the inhibitor and the ligand. This configuration aims to overcome the limitations of existing inhibitors by providing a more targeted approach with reduced side effects.
The compounds are defined by specific chemical formulas, where the Mdm2 inhibitor is characterized by various substituents such as alkyl, cycloalkyl, alkenyl, alkynyl, and aryl groups. These groups can be further substituted to enhance the compound's effectiveness. The ubiquitin ligase ligand and linker group are integral to the compound's ability to bind and degrade Mdm2, potentially offering a therapeutic advantage in treating p53-inactivated cancers.
The compounds and compositions disclosed have potential applications in cancer treatment, particularly for tumors that exhibit resistance to current Mdm2 inhibitors. By targeting Mdm2 more effectively and reducing associated toxicities, these compounds could provide a new therapeutic pathway for patients with various types of cancer, including those with p53 mutations or deletions.