Piperidine Inhibitors Disrupt Menin-MLL Binding
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Solution Overview
Problem
Current treatments for Mixed Lineage Leukemia (MLL) are ineffective due to the complexity of chromosomal rearrangements and the leukemogenic activity of MLL oncoproteins, which depend on their association with menin, making it challenging to develop targeted therapeutic approaches.
Innovation Solution
Development of piperidine-containing compounds that inhibit the binding of menin with MLL and MLL fusion proteins, specifically designed to disrupt the interaction between menin and MLL oncoproteins, thereby inhibiting leukemic cell proliferation and promoting differentiation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatment protocols are used for MLL leukemia, then treatment is administered, but the prognosis remains poor with 5-year survival ratio stagnated around 35%
Solution Approach 1:
The patent identifies menin as a critical leukemogenic cofactor that mediates the leukemogenic activity of MLL fusion proteins. By targeting the menin-MLL interaction interface with small molecule inhibitors, the patent disrupts this intermediary relationship, leading to inhibition of leukemic cell proliferation and induction of differentiation, thereby improving prognosis and survival rates.
2Productivity
If MLL fusion proteins are expressed, then leukemic transformation is promoted, but the complexity of chromosomal rearrangements makes targeted treatment challenging
Solution Approach 1:
The patent extracts the common functional domain (N-terminal domain containing menin binding motifs) from diverse MLL fusion proteins resulting from different chromosomal rearrangements. By focusing on this conserved region that interacts with menin, the patent simplifies the therapeutic target despite the complexity of underlying chromosomal rearrangements, enabling unified treatment across different MLL leukemia subtypes.
Solution Approach 2:
The patent develops small molecule inhibitors that universally target the menin-MLL interaction interface, making them effective across multiple MLL fusion types (e.g., MLL-AF4, MLL-AF9, MLL-ENL) and wild-type MLL. This universal mechanism of action allows a single drug class to address the leukemogenic activity of diverse MLL oncoproteins generated by different chromosomal rearrangements.
3Ease of operation
If menin is depleted, then HOX gene expression is down regulated and differentiation is revived, but the loss function of menin is closely tied with human neoplasms in multiple endocrine organs
Solution Approach 1:
The patent applies local quality by selectively disrupting the menin-MLL interaction in leukemic cells while preserving menin function in normal tissues. The small molecule inhibitors specifically target the MLL binding interface on menin, allowing menin to maintain its tumor repressor function in endocrine organs while preventing its leukemogenic cofactor function with MLL fusion proteins, thus achieving selective differentiation without global loss of menin.
Data Source
AI summary
The present invention relates generally to compounds that inhibit the binding of menin and MLL or MLL fusion proteins and methods of use thereof. In particular embodiments, the present invention provides compositions comprising piperidine-containing compounds and methods of use thereof to inhibit the interaction of menin with MLL oncoproteins (e.g., MLL1, MLL2, MLL-fusion oncoproteins), for example, for the treatment of leukemia, solid cancers, diabetes, and other diseases dependent on activity of MLL1, MLL2, MLL fusion proteins, MLL-PTD and/or menin.