SEC Disrupting Small Molecules for Cancer Therapy

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Solution Overview

Problem

Current inhibitors of transcription elongation affect all RNA Polymerase II transcribed genes equally, lacking specificity in targeting genes with high transcription levels such as Myc, MLL-fusion proteins, and HIV Tat target genes, which are crucial for cancer and viral replication.

Innovation Solution

Development of compounds that disrupt the Super Elongation Complex (SEC) by interfering with the interaction between AFF4 and the Cyclin T subunit of P-TEFb, specifically inhibiting the SEC components to reduce the expression of Myc and MLL chimera target genes and attenuate HIV transcription.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If existing inhibitors of transcription elongation are used, then all RNA Polymerase II transcribed genes are inhibited equally, but this lacks specificity in targeting genes with high transcription levels such as Myc, MLL-fusion proteins, and HIV Tat target genes

Engineering Contradiction:

Improvespecificity in targeting genesVSAvoidoverall Pol II processivity

Core Design Contradiction:

Adaptability or versatilityVSProductivity

Solution Approach 1:

The patent applies local quality by designing compounds that specifically target the Super Elongation Complex (SEC) components AFF4 and Cyclin T, which are locally involved in transcription elongation of specific gene sets. This selective targeting allows inhibition of high-transcription genes like Myc, MLL-fusion proteins, and HIV Tat target genes while preserving other Pol II transcriptional activities, thus achieving gene-specific control without globally suppressing all transcription.

Inventive Principle:

Principle #3Local quality

2Adaptability or versatility

If SEC components are disrupted to specifically inhibit high-transcription genes, then specificity is improved, but overall Pol II processivity is reduced

Engineering Contradiction:

Improvespecificity in targeting genesVSAvoidoverall transcription function

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The compounds selectively disrupt the SEC complex at specific interaction interfaces between AFF4 and Cyclin T, localizing the inhibitory effect to transcription elongation of specific gene sets. This localized disruption achieves specificity for high-transcription genes while maintaining other transcriptional functions through preserved Pol II activity on non-SEC-dependent genes.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent uses the SEC complex as an intermediary target rather than directly inhibiting Pol II or individual genes. By disrupting the SEC mediator complex, the compounds indirectly control transcription elongation of specific gene sets, achieving specificity through the selective disruption of this intermediate complex rather than direct global inhibition.

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS11453640B2Small molecules for disrupting the super elongation complex and inhibiting transcription elongation for cancer therapy

Publication Date: 2022.09.27 NORTHWESTERN UNIV

AI summary

Disclosed are compounds which may be utilized to inhibit transcription by RNA Polymerase II (Pol II), and in particular to disrupt the Super Elongation Complex (SEC). The compounds may be utilized in pharmaceutical compositions and methods for treating diseases and disorders associated with the biological activity of SEC, and in particular, diseases and disorders that are associated with high levels of expression of genes whose expression is SEC-dependent and that promote, support, or otherwise are required for the disease or disorder such as cancers.