PHD Reader Domain Polypeptides for Lower-Side-Effect Cancer Therapy

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Solution Overview

Problem

Existing cancer therapies often have side effects due to enhancing the writer function of histone modifier proteins, while enhancing the reader function offers fewer side effects and new therapeutic targets.

Innovation Solution

A polypeptide comprising the PHD1 and PHD2 domains of PHF6 or DPF3b, with variants, designed to function as both a reader and a writer, allowing for reversible modulation and control of therapeutic intensity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If the writer function of histone modifier proteins is enhanced, then cancer treatment effectiveness is improved, but side effects increase

Engineering Contradiction:

Improvecancer treatment effectivenessVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The invention divides the histone modifier protein into separate functional domains: the reader domain (PHD fingers) is isolated from the writer domain (ubiquitin ligase activity). This segmentation allows the reader domain to be used independently to recognize H2BK12ac marks without triggering the harmful writer function, thereby achieving cancer treatment effectiveness while eliminating side effects associated with enhanced writer activity

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention extracts the reader domain (PHD1 and PHD2 fingers) from the full-length PHF6 protein, separating it from the C-terminal ubiquitin ligase domain. This extraction enables the use of the reader function alone to target cancer cells through recognition of specific histone modifications, avoiding the harmful effects of uncontrolled writer activity that would occur if the full protein were used

Inventive Principle:

Principle #2Taking out (Extraction)

2Adaptability or versatility

If the reader function is enhanced, then new therapeutic targets are identified and side effects are reduced, but therapeutic intensity control becomes more challenging

Engineering Contradiction:

Improvetherapeutic target diversityVSAvoidtherapeutic intensity control

Core Design Contradiction:

Adaptability or versatilityVSEase of operation

Solution Approach 1:

The engineered polypeptide maintains the universal recognition capability of the PHD domains for H2BK12ac marks while enabling multiple therapeutic applications. The reader domain can be used in various cancer types and can be combined with different delivery systems or targeting moieties, providing therapeutic versatility while maintaining ease of control through the well-characterized epigenetic marking system

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The invention controls therapeutic intensity by modifying parameters of the reader domain construct, such as the specific combination of PHD domains (PHD1, PHD2), the presence of linkers, and the expression level. These parameter changes allow fine-tuning of the therapeutic effect while maintaining the ability to target diverse cancer types through the conserved H2BK12ac mark

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20260028380A1Polypeptides comprising histone code reader domains and uses thereof

Publication Date: 2026.01.29 KOREA ADVANCED INST OF SCI & TECH

AI summary

The present invention relates to a polypeptide comprising a histone code reader domain and uses thereof, in particular to a polypeptide comprising the PHD domain of PHF6 (PHD finger protein 6), optionally DPF3b (double PHD fingers 3b) or BPTF (bromodomain PHD finger transcription factor) or variants thereof, and uses thereof for the prevention or treatment of cancer.