Menin–MLL Interaction Inhibitors for MLL-Fusion Leukemia
Solution Overview
Problem
Current therapies for leukemias involving MLL fusion proteins, such as acute myeloblastic leukemia (AML) and acute lymphoblastic leukemia (ALL), have a dismal prognosis, with less than a 40% five-year survival rate, necessitating a novel therapeutic strategy to target the interaction between menin and MLL fusion proteins.
Innovation Solution
Development of compounds that non-covalently or covalently bind to menin to inhibit its interaction with MLL1, MLL2, and MLL-fusion oncoproteins, thereby disrupting the oncogenic activity of these proteins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies are used for leukemias involving MLL fusion proteins, then treatment is provided, but the prognosis remains dismal with less than 40% five-year survival rate
Solution Approach 1:
The patent extracts and targets the critical menin-MLL interaction interface to disrupt the oncogenic activity. By developing compounds that specifically bind to menin and prevent its interaction with MLL fusion proteins, the harmful oncogenic function is separated and eliminated while maintaining normal cellular functions.
Solution Approach 2:
The patent introduces small molecule compounds as intermediary agents that bind to menin and block its interaction with MLL fusion proteins. These compounds act as mediators that disrupt the harmful protein-protein interaction without directly targeting the MLL fusion proteins themselves, thereby achieving therapeutic effect.
2Object-generated harmful factors
If menin-MLL interaction is inhibited, then oncogenic activity is disrupted, but new therapeutic compounds must be developed
Solution Approach 1:
The patent employs structure-activity relationship (SAR) analysis to systematically modify molecular parameters of compounds binding to menin. By changing structural parameters such as functional groups, molecular size, and binding affinity, the patent optimizes the compounds for effective menin-MLL interaction inhibition while considering manufacturability and pharmacological properties.
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
Inhibiting the menin-MLL interaction provides a potential therapeutic approach to treat leukemias and other diseases dependent on MLL activity, offering a novel strategy to disrupt the up-regulation of oncogenes like HOX and MEIS1, potentially improving treatment outcomes.
Implementation Method 1
a compound of the disclosure covalently binds menin and inhibits the interaction of menin with MLL
Implementation Method 2
a compound of the disclosure interacts non-covalently with menin and inhibits the interaction of menin with MLL
Data Source
AI summary
The present disclosure provides compositions and methods of use to inhibit the interaction of menin with MLL1, MLL2 and MLL-fusion oncoproteins. The compositions and methods of use are useful for the treatment of leukemia, solid cancers, diabetes and other diseases dependent on activity of MLL1, MLL2, MLL fusion proteins, and/or menin.