PARP-1 PROTAC Degradation Without Protein Trapping
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Solution Overview
Problem
Conventional PARP inhibitors face issues with drug resistance, side effects such as blood toxicity, and inability to effectively degrade PARP protein, leading to limited clinical efficacy in treating cancers like breast cancer associated with BRCA mutations.
Innovation Solution
Development of a novel PARP-PROTAC compound that covalently binds to PARP-1, utilizing an E3 ubiquitin ligase binding moiety to induce targeted degradation of PARP-1, thereby inhibiting its function without causing protein trapping, thus overcoming resistance and reducing side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional PARP inhibitors are used, then PARP protein binding is achieved, but drug resistance occurs and PARP protein content cannot be reduced
Solution Approach 1:
The invention extracts the harmful trapping effect from PARP inhibition by using PROTAC mechanism that selectively degrades PARP protein without causing permanent trapping. The PROTAC compound binds to PARP and recruits E3 ubiquitin ligase to target PARP for proteasomal degradation, removing the protein from the system rather than permanently trapping it.
Solution Approach 2:
The invention changes the mechanism from conventional inhibition to protein degradation. By modifying the molecular mechanism from blocking PARP function to actively degrading PARP protein through PROTAC, the system achieves reduced PARP protein content while maintaining inhibition effectiveness.
2Reliability
If conventional PARP inhibitors are used, then PARP function is blocked, but blood toxicity and side effects occur
Solution Approach 1:
The invention extracts the harmful trapping effect that causes blood toxicity by using a different mechanism. PROTAC compounds induce targeted degradation of PARP through E3 ubiquitin ligase recruitment without causing the permanent trapping effect that leads to thrombocytopenia and other blood toxicities.
Solution Approach 2:
The invention converts the harmful permanent trapping effect into a beneficial temporary degradation effect. Instead of permanently trapping PARP which causes toxicity, the PROTAC mechanism provides temporary, controlled degradation that maintains inhibition effectiveness while reducing harmful side effects.
3Reliability
If conventional PARP inhibitors are used, then single-strand repair is blocked, but synthetic lethal effect is limited and clinical efficacy is insufficient
Solution Approach 1:
The invention extracts the limitation of conventional inhibitors by using PROTAC-mediated degradation. This mechanism provides more potent and sustained PARP protein reduction, enhancing the synthetic lethal effect in HRD tumor cells and improving clinical efficacy in treating BRCA-mutated cancers.
Solution Approach 2:
The invention changes the mechanism from conventional inhibition to protein degradation, achieving more effective PARP protein reduction. This parameter change in the mechanism of action leads to enhanced synthetic lethal effect and improved clinical efficacy in treating cancers with HRD.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The PARP-PROTAC agent demonstrates high selectivity and safety, providing effective PARP-1 degradation with improved pharmacokinetic characteristics, offering a promising therapeutic approach for treating PARP-1-mediated diseases like breast, ovarian, and uterine cancers.
Implementation Method 1
L is a bond or chemically linking moiety that covalently couples the PTM and ULM; the L of the present invention forms a covalent bonding, including single covalent bonding or multiple covalent bonding, with PTM and ULM at any site
Implementation Method 2
PARP-PROTAC blocks the catalytic and scaffolding functions of PARP1 without causing PARP1 trapping... effectively degrade PARP protein
Data Source
AI summary
A compound represented by formula (I), a stereoisomer, deuterated compound, solvate, pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition containing them, and use of the compound as a PARP-1 inhibitor in the preparation of a drug for treating related diseases, each group in the formula (I) being as defined in the description.