PROTAC Compounds Degrade ER, AR, and BRD Proteins
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Solution Overview
Problem
Current therapies for treating cancers driven by estrogen receptor (ER), androgen receptor (AR), and bromodomain (BRD) containing proteins are limited by side effects and the development of resistance.
Innovation Solution
Development of novel compounds, specifically PROteolysis-TArgeting Chimeras (PROTACs), that recruit E3 ubiquitin ligases to target ER, AR, and BRD proteins for ubiquitination and degradation, thereby inhibiting their signaling pathways.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current antiestrogen therapies (aromatase inhibitors, SERMs, SERDs) are used to treat ER+ breast cancer, then estrogen-mediated cellular proliferation is inhibited, but patients develop resistance and experience harmful side effects
Solution Approach 1:
The patent employs PROTAC molecules as intermediary compounds that facilitate the degradation of ERα proteins. These PROTACs consist of three components: an ERα ligand binding domain, an E3 ligase binding domain, and a linker connecting them. The intermediary PROTAC recruits E3 ubiquitin ligases to target ERα for ubiquitination and subsequent proteasomal degradation, thereby eliminating the need for direct ERα inhibition and overcoming resistance mechanisms.
Solution Approach 2:
The invention changes the fundamental parameter of ERα protein levels by inducing their degradation rather than merely inhibiting their activity. By using PROTACs that trigger ubiquitination and proteasomal degradation, the patent reduces ERα protein levels to undetectable amounts, representing a qualitative change from inhibition to elimination, thereby overcoming resistance to conventional therapies.
2Quantity of substance
If SERDs like fulvestrant are used to downregulate ERα, then receptor levels decrease, but pharmacokinetic properties are poor and only half downregulation is achieved after 6 months
Solution Approach 1:
The patent uses PROTAC molecules as intermediaries to achieve more effective ERα downregulation. The PROTAC structure includes an ERα ligand binding domain that targets the receptor, an E3 ligase binding domain that recruits degradation machinery, and a linker that connects them. This intermediary mechanism achieves complete ERα degradation, surpassing the partial downregulation (50% after 6 months) achieved by fulvestrant.
3Reliability
If direct BET inhibitors are developed to treat uncontrolled cell growth, then cellular proliferation is inhibited, but potency is limited
Solution Approach 1:
The patent applies PROTAC technology to BET proteins, creating PROTAC molecules that recruit E3 ubiquitin ligases to target BET proteins for degradation. This intermediary degradation mechanism achieves complete elimination of BET proteins, providing superior potency compared to direct BET inhibitors that only partially inhibit their function.
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 use of these PROTACs effectively inhibits the signaling pathways of ER, AR, and BRD proteins, offering a potential solution to the limitations of current cancer therapies by enhancing treatment efficacy and reducing side effects.
Implementation Method 1
PROTeolysis-TArgeting Chimeras (PROTACs), that recruit E3 ubiquitin ligases to target ER, AR, and BRD proteins for ubiquitination and degradation
Data Source
AI summary
Compounds, pharmaceutical compositions containing such compounds, and their use in prevention and treatment of cancer and other related diseases and conditions are disclosed. In an embodiment, the disclosed compounds have the following Formula (I) and pharmaceutically acceptable salts thereof: