Qualigen have developed a direct inhibitor of RAS with a predicted unique interaction region capable of directly binding to wild-type H- and K-RAS, but which shows preferential binding for KRAS G12D and G12C mutants. This novel inhibitor disrupts the RAS effector domain and blocks the ability of RAS to signal through its effectors.
Data from preclinical studies were presented in a poster session at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. Qualigen used in silico virtual library screening to identify an initial candidate inhibitor that was effective at inhibiting the 3D growth of PDAC cells without affecting their growth in 2D. Subsequent iterative rounds of medicinal chemistry were then performed to identify a series of derivatives with enhanced activity, as determined by 3D growth inhibition assays and effects on Ras signaling, as determined by Western blot analysis of phosphor-ERK, phosphor-Akt and activation of Ral A.
The results showed that the series of RAS inhibitors effectively block PDAC cell growth in 3D without impacting their 2D proliferation and suppress the interaction of KRAS with its effector cRAF. The inhibitors also effectively inhibit RAS signaling in mutant RAS-containing PDAC cells. Since these novel compounds are predicted to bind to RAS at a different site to either AMG-510 (G12C specific inhibitor) or MRTX-1133 (G12D specific inhibitor), the company tested the co-operativity of our compounds with these existing agents. These compounds enhanced the anti-proliferative effects of both MRTX-113 and AMG-510 in mutant KRAS G12D and G12C PDAC cells, respectively.
KOL insights
“Qualigen's pan-RAS inhibitor platform comprises a group of small molecules specifically developed to hinder the interaction between mutated RAS gene proteins and their effector proteins. These compounds have demonstrated their ability to impede tumor growth in several in vivo models. Qualigen is actively assessing the potential of these promising compounds, derived from this collaborative effort, in the treatment of various advanced solid tumors driven by RAS mutations, including pancreatic, breast, colorectal, and lung cancers.”–Expert Opinion.
Conclusion
The poster presents findings on the simultaneous administration of Qualigen's pan-RAS inhibitor molecules with commonly used therapeutics for pancreatic cancer. Through in vivo experiments using xenograft models and patient-derived xenograft (PDX) models, the study confirmed the effectiveness of these molecules. The results demonstrated that the pan-RAS inhibitors synergize with AMG-510 (sotorasib), a G12C-specific inhibitor, and MRTX1133, a G12D-specific inhibitor, against pancreatic cancer cell lines. Furthermore, the agents displayed the ability to suppress resistance to MRTX1133 in laboratory tests, suggesting that these pan-RAS compounds might overcome resistance to AMG-510 and MRTX1133 in live subjects
