Pyrimidine-Based KRAS G12D Modulators for GDP-State Stabilization
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Solution Overview
Problem
Current therapies are ineffective against KRAS G12D mutations in cancer due to the slow intrinsic rate of GTP hydrolysis and lack of selective inhibitors that can stabilize the inactive GDP-bound state, making it difficult to target the active GTP-bound state for therapeutic intervention.
Innovation Solution
Development of pyrimidine-based compounds that selectively bind to the active GTP-bound state of KRAS G12D, stabilizing a conformation incompetent for oncogenic signaling interactions and inhibiting MAPK signaling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule inhibitors are designed to block effector binding or restore GAP sensitivity, then selective inhibition of KRAS-driven cancers is achieved, but such inhibitors have not been identified despite extensive efforts
Solution Approach 1:
Instead of attempting to inhibit the active GTP-bound state of KRAS (the conventional approach), the patent inverts the strategy by designing compounds that selectively stabilize the inactive GDP-bound state. This inversion allows the compound to exploit the conformational differences between active and inactive states, achieving selective inhibition of mutant KRAS while sparing wild-type Ras function.
Solution Approach 2:
The patent employs parameter changes by modifying the nucleotide state stabilization - specifically stabilizing the GDP-bound conformation rather than the GTP-bound conformation. The compound alters the equilibrium between GTP-bound and GDP-bound states, shifting it toward the inactive GDP state, thereby achieving therapeutic effect through conformational parameter modification.
2Reliability
If KRAS G12D mutation is targeted, then oncogenic signaling is inhibited, but the slow intrinsic rate of GTP hydrolysis makes it difficult to trap in inactive state
Solution Approach 1:
The compound performs preliminary action by preemptively stabilizing the inactive GDP-bound state before GTP can bind or before the slow hydrolysis process can occur. By locking KRAS G12D in the inactive conformation, the compound prevents the transition to the active state, effectively bypassing the slow hydrolysis rate limitation.
Solution Approach 2:
The patent exploits the dynamic conformational transitions of KRAS between GTP-bound and GDP-bound states. The compound dynamically stabilizes one conformation (GDP-bound) while allowing the natural flexibility of the protein to remain, achieving inhibition without rigidifying the entire structure.
3Reliability
If covalent modification is used for KRAS G12C inhibition, then selective binding is achieved, but KRAS G12D lacks cysteine for covalent chemistry
Solution Approach 1:
The patent uses the nucleotide-binding pocket and surrounding residues as an intermediary mechanism for selective binding. Instead of relying on direct covalent modification of the mutation site (which requires cysteine), the compound mediates selectivity through non-covalent interactions with the GDP-bound conformation, which is structurally distinct in mutant KRAS versus wild-type Ras.
Solution Approach 2:
The patent replaces the mechanical covalent bonding mechanism (which works for G12C) with a non-covalent conformational stabilization mechanism. This substitution allows the same compound to achieve selective binding through structural recognition rather than chemical reactivity, making it applicable to G12D and potentially other mutations lacking cysteine.
4Reliability
If inhibitors stabilize inactive GDP-bound state, then selective inhibition is achieved, but this approach has not yielded clinically effective therapies
Solution Approach 1:
The patent applies local quality by targeting specific local features of the inactive GDP-bound state that are unique to mutant KRAS. The compound interacts with local structural elements (such as the switch regions and nucleotide-binding pocket conformation) that differ between mutant and wild-type, achieving selectivity through localized structural recognition rather than global protein properties.
Data Source
AI summary
Provided herein are compounds, such as compounds of Formula (I), Formula (I-A), Formula (I-B), or pharmaceutically acceptable salts of any one there, useful for modulating KRAS GD12 and/or other G12 mutants.