MLLT1 and MLLT3 PROTAC Degraders for Selective Cancer Targeting
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Solution Overview
Problem
Current drug discovery efforts have yielded weak modulators for targeting the MLLT1 and MLLT3 proteins, which are critical drivers of various cancers, necessitating the development of potent compounds to induce their selective degradation.
Innovation Solution
The development of a series of PROTAC compounds that selectively target and degrade MLLT1 and/or MLLT3 proteins by binding to their YEATS domains, utilizing an E3 ubiquitin ligase to induce proteolysis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current drug discovery efforts are used to target MLLT1 and MLLT3 proteins, then some modulating activity is achieved, but the potency is weak and insufficient for effective cancer treatment
Solution Approach 1:
The PROTAC compound is segmented into three functional modules: (1) an MLLT1/MLLT3 binder moiety that specifically recognizes the target protein, (2) a linker moiety that connects the binder to the E3 ligase recruiter, and (3) an E3 ligase recruiter moiety that recruits the ubiquitin ligase system. This segmentation allows each module to independently perform its function while working together to achieve potent target degradation, resolving the contradiction between modulating activity and potency.
2Reliability
If PROTAC compounds are designed to induce selective degradation of MLLT1 and MLLT3, then therapeutic efficacy is improved, but the complexity of compound design and synthesis increases
Solution Approach 1:
The linker moiety serves as an intermediary component that bridges the MLLT1/MLLT3 binder and the E3 ligase recruiter. This intermediary structure facilitates the formation of a ternary complex between the target protein, the PROTAC compound, and the E3 ubiquitin ligase, enabling selective degradation while managing the structural complexity through modular design.
Solution Approach 2:
The PROTAC compound design employs universal building blocks that can be combined in different configurations to target multiple MLLT family members (MLLT1, MLLT3, and other FET family proteins). The modular architecture allows a single platform to address multiple therapeutic targets, reducing overall design complexity while maintaining high therapeutic efficacy.
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
These PROTAC compounds effectively inhibit and degrade the MLLT1 and MLLT3 proteins, providing a potential therapeutic approach for treating cancers such as leukemia and solid tumors.
Implementation Method 1
Proteolysis targeting chimeras (PROTACs) have been proposed as a small molecule-based platform technology capable of inducing proteolysis of a target protein in the body. The PROTAC is a bifunctional compound in which a molecule that binds to a disease-related target protein and an E3 ubiquitin ligase binding moiety are linked by a chemical linker.
Implementation Method 2
The PROTAC is a bifunctional compound in which a molecule that binds to a disease-related target protein and an E3 ubiquitin ligase binding moiety are linked by a chemical linker. Theoretically, the PROTAC compound is capable of inducing degradation of the target protein by placing the disease-related target protein near the E3 ubiquitin ligase.
Data Source
AI summary
The invention relates to a compound which is a Proteolysis Targeting Chimera (PROTAC) or a pharmaceutically acceptable salt thereof, wherein the PROTAC has the structure: M-LINK-U wherein U is an E3 ubiquitin ligase binding moiety, LINK is a moiety that covalently links M and U, and M is an MLLT1 and/or MLLT3 binder of formula (I): wherein: wherein Z1, Z2, Y1, Y2, Y3, R1, R2, R8, X, L and Hy are as defined herein, and either R8 is a bond to LINK, or M is bonded to LINK via a C or N atom within group R8 or ring Hy such that a hydrogen atom on the C or N atom within group R8 or ring Hy is replaced with a bond to LINK. The compounds are useful in the treatment of cancer.