Patent Title: Novel DNA Polymerase Gamma Inhibitor and Uses Thereof
IP Status: Granted US and European patents; filing/protection coverage reported for Türkiye, France, Germany and the United Kingdom
Technology Area: Cancer Therapeutics / Small-Molecule Drugs / Synthetic Lethality / DNA Repair Targets
TRL: TRL 4
This technology uses small-molecule DNA polymerase gamma (Pol γ) inhibitors to selectively target cancer cells carrying MLH1 mutations or loss of MLH1 function through a synthetic-lethality mechanism. Developed particularly for colorectal cancers with impaired MLH1 function, the approach exploits increased dependence on mitochondrial DNA-repair pathways and provides a molecularly targeted platform for anticancer drug development.
Technology Overview
The technology is based on the synthetic-lethal relationship between impaired MLH1 function, a key component of the DNA mismatch-repair pathway, and mitochondrial DNA polymerase gamma (Pol γ). Mutation or loss of MLH1 function compromises one DNA-repair pathway and can increase the dependence of cancer cells on complementary mechanisms required to maintain mitochondrial genome integrity. Inhibition of Pol γ disrupts this compensatory mechanism and can selectively drive cancer cells with impaired MLH1 function towards cell death.
Pol γ is a central enzyme involved in mitochondrial DNA replication and base-excision repair. The developed inhibitor compounds directly interact with Pol γ and suppress its DNA-synthesis activity. This interference promotes accumulation of mitochondrial DNA damage, increased reactive oxygen species, mitochondrial dysfunction and ultimately cell death in cancer cells with impaired MLH1 function.
A key differentiating feature is the use of a molecular vulnerability associated with MLH1 mutation or loss of function rather than relying solely on broad cytotoxicity. Laboratory and animal studies showed inhibition of proliferation and tumour growth in HCT116 colorectal cancer models with impaired MLH1 function, while MLH1-functional control cells and tumour models were substantially less affected or unaffected under the reported experimental conditions.
The patent scope includes Pol γ inhibitor compounds, pharmaceutically acceptable salts or prodrugs, and pharmaceutical compositions containing these compounds. The approach may be developed as a standalone therapy or investigated in combination with other anticancer agents or radiotherapy.
Current development remains at laboratory and preclinical stage. Further translation requires optimisation of the candidate compound and formulation, completion of the necessary safety and pharmacology studies, and subsequent clinical evaluation in patient populations selected according to MLH1 mutation or functional status.
Problem / Market Need
Mutations in MLH1 or loss of MLH1 function can disrupt the DNA mismatch-repair system and represent an important molecular feature in defined subsets of colorectal and other cancers. These tumours may exhibit distinct responses to standard therapies, creating a need for treatment strategies that directly exploit their underlying molecular vulnerabilities.
When tumour cells lose the function of a primary DNA-repair pathway, they may become increasingly dependent on alternative or complementary repair mechanisms for survival. Synthetic-lethality strategies exploit this dependency by inhibiting a second pathway that has become critical specifically in the repair-impaired cancer cell.
Targeting Pol γ in cancer cells with impaired MLH1 function provides such an approach, creating the potential for a precision-oncology strategy directed towards tumours defined by their MLH1 status rather than applying a broadly cytotoxic mechanism across all cells.
Key Advantages
- Synthetic-lethality-based targeting of cancer cells with MLH1 mutation or loss of function
- Direct molecular targeting of mitochondrial DNA polymerase gamma
- Exploits DNA-repair dependency associated with impaired MLH1 function
- Antitumour activity demonstrated in laboratory and animal models
- Potential selectivity relative to control cells and tumours with functional MLH1
- Small-molecule architecture suitable for pharmaceutical development
- Potential for standalone or combination anticancer treatment strategies
- Compatible with biomarker-driven precision-oncology development
Applications
- Targeted therapy development for colorectal cancers with MLH1 mutation or loss of function
- Small-molecule therapies for tumours with impaired mismatch-repair function
- Synthetic-lethality-based cancer therapeutics
- Precision-oncology approaches targeting DNA-repair vulnerabilities
- Combination therapy development for tumours with impaired MLH1 function
- Preclinical drug development for Lynch-syndrome-associated cancers
- Anticancer drug research targeting mitochondrial DNA repair
Relevant Industries
- Oncology
- Pharmaceuticals and Biopharmaceuticals
- Small-Molecule Drug Development
- Precision Medicine
- Cancer Biology
- Preclinical and Clinical Drug Development
- Molecular Diagnostics and Patient Stratification
Technology Readiness Level & Validation
Technology Readiness Level: TRL 4
The mechanism has been demonstrated through cellular studies, and preclinical evaluation has been performed in animal models. In HCT116 colorectal cancer cells with impaired MLH1 function, Pol γ inhibition reduced proliferation and induced selective cell death.
Animal studies using HCT116 xenograft models with impaired MLH1 function demonstrated suppression of tumour growth, while comparable effects were not observed in the control tumour models with functional MLH1 used in the reported studies. These findings support the MLH1-status-dependent antitumour mechanism of the technology.
The Technology Form states that validation remains in progress, that animal studies have been completed, and that clinical studies have not yet begun. No industrial or clinically deployable product prototype is currently available.
Advancement beyond TRL 4 will require development of a clinical candidate, broader safety and pharmacology studies, and progression into clinical trials.
The technology was developed as an output of a TÜBİTAK 1003-supported research project.
Intellectual Property
US Patent: US11883419B2
US Patent Publication: US20210275548A1
European Patent: EP3810147B1
International Patent Publication: WO2020005171A1
Patent Title: Novel DNA Polymerase Gamma Inhibitor and Uses Thereof
US Filing Date: 25 June 2018
US Patent Grant Date: 30 January 2024
Applicants / Assignees: Acibadem Mehmet Ali Aydinlar University, Sabancı University and Koç University
Protection / Filing Coverage Reported in the Technology Form: United States, Türkiye, France, Germany, United Kingdom
Commercialisation Status
The technology is currently in prototype development and is available for licensing. Further development requires translation of the preclinically demonstrated selective antitumour mechanism into a clinically suitable drug candidate and pharmaceutical formulation.
Collaboration Opportunities
- Licensing
- Scientific consultancy
- Joint R&D and co-development
- Industrial and preclinical validation
- Manufacturing and drug-development collaboration
- Investment and commercial partnership
- Clinical-development partnership
Potential partners may include oncology-focused biotechnology and pharmaceutical companies developing small-molecule therapeutics, organisations targeting DNA-repair pathways, precision-oncology companies, CROs with preclinical and clinical development capabilities, and diagnostic companies working on MLH1/MMR-based patient stratification.
Priority areas for joint development include candidate optimisation, pharmaceutical formulation, GLP-compliant toxicity and pharmacokinetic studies, advanced validation in tumour models with MLH1 mutation or loss of function, biomarker strategies for patient selection, and preparation of early-phase clinical development programmes.
Inventors
Inventors: Meltem Muftuoglu, Batu Erman, Burak Erman
Contact
For licensing, preclinical or clinical development, joint R&D or other collaboration opportunities related to this technology, please contact Sabancı University Technology Transfer Office (SUATT) at dpe.suatt@sabanciuniv.edu.