Mutated KRAS Inhibition and
Degradation Novel Small Molecule
ABREV001: Highlights of a Champion
KRAS Small Molecule
Agastiya Biotech is actively engineering small molecules that have the potential to destroy mutated oncogenes while leaving healthy, normal genes unaffected. Our lead small molecule, ABREV001, promises to be a First-in-Class pan-mutated KRAS inhibitor and degrader that uniquely binds to at the active GTP binding site.
KRAS is one of the most frequently mutated oncogenes in cancer, being a potent initiator of tumorigenesis, a strong inductor of malignancy, and a predictive biomarker of response to therapy. In addition to holding this distinction, unsuccessful attempts to target this protein have led to the characterization of RAS as ‘undruggable’. RAS signaling networks are built at the membrane of cells, bridging extracellular cues into cellular events, such as cell growth, proliferation, differentiation, and survival, having a decisive role in the transition of healthy cells to cancer. All these findings have led the scientific community to exploit RAS or its downstream effectors as therapeutic targets, hoping to impair tumor growth and survival. However, no effective KRAS directed signaling inhibition has been successfully achieved.
The promising preclinical findings of ABREV001 include:
- 95% tumor volume reduction in vivo starting from Day 9 culminating within 28 days. No relapse throughout 90 Day study.
- Novel inhibitor that binds to the GTP pocket in mutant KRAS.
- Mutation types: G12C, G12D, G12V, G13D (NSCLC, CRC, Pancreatic)
- Prevents downstream signalling and activates the proteasomal degradation pathway, triggering apoptotic cell death pathways resulting in degradation of mutant KRAS.
- Minimum or no toxicity in vitro and in vivo.
- Indicative of inhibitory effects on cancer stem cells pathways.
KRAS Pathway and Mechanism of Action
Lead Program ABREV001
- Induces apoptosis in KRAS-dependent cancer cell lines
- ABREV001 inhibits KRAS mutant expressing cancer cells
- Blocked GTP-KRAS Formation in KRAS Mutant cells
- Inhibition of KRAS Downstream Signaling Pathway
- ABREV001 suppresses tumor growth in xenograft Model
ABREV001: Mutant and Wild Type KRAS
ABREV001 Inhibits Ras-GTP Complex Formation: Mutant and Wild Type
- Formation of GTP-KRAS was inhibited in KRAS mutant cells compared to total amount of KRAS
- ABREV001 selectively targets mutant form of KRAS
- No effect was observed in Wild Type KRAS
Colony Formation Assay Mutant and Wild Type
- Colony formation was reduced in Mutant KRAS cells after treatment with ABREV001 compared with control.
- No reduction was observed in KRAS WT
Degradation of KRAS and Downstream Effectors
Degradation of KRAS Mechanism
- ABREV001 degrades the RAS via GSK3β phosphorylation through cross talk mechanism with Wnt/β-catenin pathway via its negative regulators such as APC, Axin and glycogen synthase kinase 3β (GSK3β).
- Activated GSK3β phosphorylates both β-catenin and K-Ras at S33/S37/T41 and T144/T148 respectively
- When the Wnt/β-catenin signaling is negatively regulated, the Ras degradation occurs together with the β-catenin degradation
- The phosphorylated proteins were degraded via β-TrCP E3 linker-mediated polyubiquitinylation dependent proteasomal degradation
- Amounts of both β-catenin and Ras proteins are often increased especially in metastatic cancer involving cancer stem cell activation