A novel RAS inhibitor for pancreatic ductal adenocarcinoma.

Abstract

e16263 Background: Pancreatic cancer has a dismal survival rate and no good therapeutic options. Of all types of cancer, it is Pancreatic cancer that is most closely associated with activating mutations in the RAS oncoprotein. Approximately 90% of pancreatic adenocarcinomas carry point mutations activating RAS. Ras directed targeted therapy is the obvious approach to enhancing treatment options for the disease. There is now an FDA approved targeted RAS therapeutic specific to the RAS12C mutant form. However, this particular mutation is uncommon in Pancreatic cancer. Therefore, drugs which act more broadly on RAS are required. There are currently no approved pan-RAS inhibitors. We have developed a small molecule pan-RAS inhibitor which binds directly to all forms of RAS. It acts to block the ability of RAS and to bind and signal through its effectors. It is active in vitro and in vivo against multiple models of pancreatic cancer. Methods: In silico screening of a virtual compound library was performed to identify an initial candidate inhibitor. Iterative rounds of Medicinal Chemistry informed by structural modeling and bioassay in 3D vs 2D growth assays were performed to identify an enhanced activity derivative. Target binding was confirmed by Microscale Thermophoresis and NMR. RAS/RAF complex status was measured by co-immunoprecipitation of the endogenous proteins. Ras signaling was assayed by Western analysis of Phospho-ERK and RAL-GTP pull down assays. In vitro activity was measured using 3D soft agar assays. In vivo activity was measured by ip or po administration against pancreatic tumor cell line xenografts and pdx systems. Results: The current lead, designated RAS-F binds all three main isoforms of RAS at low uM kd and modulates the RAS effector domain in NMR studies. It suppresses RAS signaling pathways in transient assays and suppresses pancreatic tumor cell growth in soft agar with IC50s below 500nM. It suppresses xenograft development of human and mouse RAS driven pancreatic tumor cell lines and reduces the growth of a pancreatic cancer pdx. Conclusions: We have developed a pre-clinical pan-RAS inhibitor that is active in vitro and in vivo against pancreatic cancer models. Funding: NIH 5U01HL127518-03, Kentucky Lung Cancer Research Program (GJC), Qualigen Therapeutics LLC.