KRAS PROTAC Composition for Mutant Binding and Targeted Degradation
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Solution Overview
Problem
There is a need for a proteolysis targeting chimera (PROTAC) capable of binding to KRAS proteins or mutants and inducing their degradation to address KRAS-associated cancers.
Innovation Solution
Development of compounds represented by structural formulas I and III, or their pharmaceutically acceptable salts, which can bind to KRAS and induce its degradation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional PROTAC designs are used, then degradation of certain proteins is achieved, but effective binding to KRAS and induction of KRAS degradation is not achieved
Solution Approach 1:
The patent modifies the chemical structure parameters of the PROTAC molecule by incorporating specific KRAS-binding moieties with defined structural characteristics (such as glycine-rich regions and specific amino acid sequences) to enable effective binding to KRAS and its mutants, thereby achieving KRAS degradation where conventional PROTAC designs failed
Solution Approach 2:
The PROTAC molecule is constructed as a composite structure combining a KRAS-binding moiety (with specific amino acid sequences like glycine-rich regions), a recruiter moiety (such as VHL E3 ligase binder), and a linker, creating a multifunctional molecule that can simultaneously bind KRAS and recruit degradation machinery
2Object-affected harmful factors
If KRAS levels are reduced through degradation, then therapeutic effect against KRAS-associated cancers is achieved, but maintaining protein homeostasis and minimizing off-target effects becomes challenging
Solution Approach 1:
The PROTAC design incorporates a recruiter moiety that specifically targets VHL E3 ligase, creating a localized and selective degradation pathway that affects only KRAS and not other cellular proteins, thereby minimizing off-target effects while achieving therapeutic reduction of KRAS levels in cancer cells
Solution Approach 2:
The patent uses the VHL E3 ligase complex as an intermediary degradation machinery that is recruited by the PROTAC molecule to specifically degrade KRAS through the ubiquitin-proteasome pathway, providing a controlled and selective mechanism for reducing KRAS levels without directly interfering with other cellular processes
Data Source
AI summary
Provided herein are KRAS proteolysis targeting chimeras (PROTACs), compositions comprising the KRAS PROTACs, and methods of making and using the KRAS PROTACs, e.g., to promote degradation of KRAS and/or treat KRAS-associated cancers. In an embodiment, the KRAS PROTAC has the following structural formula:or a pharmaceutically acceptable salt thereof, wherein values for the variables are as described herein.