Heterocyclic Compounds for Selective Ras Mutant Signaling Reduction
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Solution Overview
Problem
Current therapies are inadequate for targeting Ras mutant cancers, particularly those with the G12C mutation, due to the high affinity of Ras proteins to GTP and lack of obvious targeting regions, limiting effective treatment options.
Innovation Solution
Development of heterocyclic compounds that can specifically target Ras mutants and associated proteins to reduce Ras pathway signaling, offering potential therapeutic and diagnostic solutions for various diseases, including cancers and neoplasia.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Ras proteins bind to GTP with high affinity, then the biological function of Ras is maintained, but targeted therapy becomes difficult due to lack of druggable pockets
Solution Approach 1:
The patent uses CRISPR-Cas13 as an intermediary molecule to indirectly target and degrade mutant Ras mRNA. Instead of attempting to bind directly to the protein-Ras-GTP complex which lacks druggable pockets, the invention introduces a nucleic acid-based intermediary (CRISPR-Cas13 system) that can recognize and cleave mutant Ras mRNA transcripts, thereby preventing translation of mutant Ras proteins without needing to access the protein binding interface
Solution Approach 2:
The invention replaces the conventional small-molecule drug approach (mechanical/chemical binding to protein pockets) with a nucleic acid-based molecular recognition system. CRISPR-Cas13 uses programmable RNA guides to recognize specific mutant Ras mRNA sequences through base-pairing, substituting the need for traditional protein-ligand or protein-small molecule interactions with a nucleic acid recognition mechanism
2Measurement precision
If G12C mutation is targeted specifically, then therapeutic precision is improved, but applicability is limited due to low prevalence rate of only 3% in PDAC
Solution Approach 1:
The CRISPR-Cas13 platform provides universal applicability across different Ras mutations (G12C, G12V, G12A, G12S, G13D, Q61H, Q61L) while maintaining mutation-specific precision. By designing different guide RNAs that target each specific mutant allele, the same CRISPR-Cas13 machinery can be adapted to treat various Ras mutation types, making the therapy universally applicable to different mutation profiles rather than being limited to a single mutation type
Solution Approach 2:
The invention changes the targeting parameter from protein-level interactions to nucleic acid-level recognition. By targeting mRNA transcripts rather than proteins, the system can distinguish between mutant and wild-type alleles through sequence-specific RNA binding, enabling precise targeting of different mutations through programmable guide RNA design rather than relying on conserved protein structural features
3Productivity
If conventional therapies are used for Ras mutant cancers, then treatment coverage is maintained, but effectiveness is insufficient due to inability to specifically target Ras pathway
Solution Approach 1:
The invention extracts and eliminates the specific problem of mutant Ras protein overexpression by using CRISPR-Cas13 to selectively degrade mutant Ras mRNA transcripts. This removes the oncogenic driver (mutant Ras) from the cancer cells specifically, rather than using conventional therapies that attempt to inhibit downstream effectors or use broad-spectrum treatments that lack specificity for the Ras mutation
Solution Approach 2:
Instead of trying to inhibit Ras protein function directly (which is difficult due to lack of druggable pockets), the invention inverts the approach by targeting the upstream nucleic acid template (mRNA) that produces the Ras protein. By degrading the mRNA before translation, the system prevents protein synthesis rather than attempting to block protein function, reversing the conventional therapeutic strategy
Data Source
AI summary
The present disclosure provides compounds and pharmaceutically acceptable salt thereof, and methods of using the same. The compounds and methods have a range of utilities as therapeutics, diagnostics, and research tools. In particular, the subject compositions and methods are useful for reducing signaling output of oncogenic proteins.