CHAMP Degraders for Tumor-Selective KRAS(G12D) Targeting
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Solution Overview
Problem
Current chemically induced targeted protein degradation (TPD) technologies face challenges such as promiscuous degradation in non-target tissues, unwanted side effects, and resistance due to mutations or alterations in the ubiquitin-proteasome system components, limiting their therapeutic efficacy, particularly for targeting KRAS(G12D) and HSP90 in cancer treatment.
Innovation Solution
Development of chaperone-mediated protein degraders (CHAMPs) that selectively bind to KRAS(G12D) and HSP90, inducing targeted protein degradation through novel protein-protein interactions, utilizing a first moiety for KRAS(G12D) binding and a second moiety for HSP90 binding, thereby promoting tumor-selective degradation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PROTAC molecules are used to induce protein degradation, then targeted protein degradation is achieved, but promiscuous degradation in non-target tissues occurs
Solution Approach 1:
The patent uses HSP90 as an intermediary component in the degradation pathway. The CHAMP molecule binds to both the target protein (KRAS(G12D)) and HSP90, utilizing the chaperone's natural client protein recognition capability to achieve tissue-selective degradation. HSP90 acts as a mediator that recognizes client proteins only in specific cellular contexts, thereby preventing promiscuous degradation in non-target tissues while maintaining effective degradation of the target protein.
2Reliability
If PROTAC molecules are used to induce protein degradation, then therapeutic efficacy is improved, but resistance due to mutations or alterations in UPS components develops
Solution Approach 1:
By introducing HSP90 as an intermediary chaperone component, the system creates a more robust degradation pathway that is less susceptible to mutations in the canonical UPS components. HSP90's role as a molecular chaperone that recognizes specific client protein features provides an alternative recognition mechanism that can bypass resistance mechanisms that affect traditional E3 ligase-PROTAC interactions.
Solution Approach 2:
The patent changes the degradation pathway parameters by shifting from direct E3 ligase-mediated degradation to HSP90 chaperone-mediated degradation. This parameter change in the degradation mechanism alters the recognition and degradation kinetics, potentially overcoming resistance that has developed against conventional PROTAC approaches targeting the same protein.
3Ease of operation
If conventional inhibitors are used, then biochemical inhibition is achieved, but target selectivity is reduced
Solution Approach 1:
The CHAMP molecule is segmented into distinct functional domains: one domain binds to the target protein (KRAS(G12D)) while another domain binds to HSP90. This segmentation allows each domain to independently recognize its specific binding partner, with the HSP90 binding providing an additional layer of selectivity that conventional single-domain inhibitors lack, thereby improving target selectivity while maintaining biochemical inhibition capability.
Data Source
AI summary
Provided are tumor-targeted protein degradation chimeras, termed chaperone-mediated protein degraders (CHAMPs) comprising a first moiety that is capable of binding to a target protein (e.g., KRAS(G12D) or proteins and a second moiety that is capable of binding a chaperone protein or proteins or protein component of chaperone complexes (e.g., HSP90). Pharmaceutical compositions comprising the disclosed CHAMPs and their uses for treating thereof, which are useful for treating cancers and related conditions are also provided.