A new RAS regulator as targeted therapy for cancers with oncogenic KRAS mutations
Advantages
- Reduces viability of tumor cells with oncogenic KRAS (IC50 80µM).
- Sinergizes with Velcade (Bortezomid) to reduces viability of tumor cells.
- No toxicity in in vivo studies (no body weight lost, none of the animals died, local inflammation of the tail).
- Reduces CRC orthotopic tumor growth in mice as SoC treatment.
Goal
The group is looking for a license agreement but other type of collaborations with industrial partners maybe considered.
Patent
WO2024141554; Priority date: 27/12/2022
Europe and USA protection extended
Reference
UBTT0465
Contact
Rosa Vázquez
Email: rvazquez@fbg.ub.edu
A new RAS regulator as targeted therapy for cancers with oncogenic KRAS mutations
Executive summary
A research group, with wide experience on Cancer Cell Biology, Organic Chemistry and Molecular Modelling has generated a new RAS regulator as targeted therapy for cancers with oncogenic KRAS mutations.
Introduction
KRAS (member of the Ras family) is a driver gene for the most aggressive cancers. KRAS is an undeniable target for pancreatic, lung, and metastatic colorectal cancer therapy, but so far it has been considered a non-druggable target. 90% of pancreatic cancers present an oncogenic mutation in KRAS. Moreover 50% of colon cancer and 30% lung cancer is because oncogenic KRAS.
Description
We defined a series of small drugs that bind to an allosteric pocket of KRAS. We synthesized a set derivative of one of the initial hits. Our candidate reduces viability of tumor cells with oncogenic KRAS (IC50 80uM) and does not have an effect on cell viability in normal cells or tumor cells without oncogenic KRAS. It also reduces CRC orthotopic tumor growth in mice as SoC treatment and synergizes with Velcade (Bortezomid) to induce cell death of tumour cells. The candidate injected intravenous in mice at 100mg/Kg does not has toxicity and reaches high concentrations in blood.
Current stage of development
- Identification of KRAS pocket.
- High-throughput screening– in-silico library of small molecules.
- Selection of one hit according to the best binding to the pocket and acquisition of this Hit and synthesis of some derivatives.
- Analysis of the effect of candidate and derivatives on Ras signaling in CRC cancer cells.
- Analysis of the effect of the candidate on CRC tumor growth in in vivo (orthotopic xenograft mouse model).