Model RAS-F - RAS Protein Inhibitors as Treatments for Advanced Solid Tumors
Our RAS-F portfolio includes lead and back-up small molecules that suppress the interaction of endogenous RAS with c-RAF, upstream of the KRAS, HRAS, and NRAS effector pathways. This potentially enables a differentiated, RAS-targeted strategy for inhibiting the MAPK, PI3K, and TOR pathways that are implicated in cancer cell proliferation, survival, and differentiation (see figure). RAS itself acts as a “hub” that activates multiple effector pathways and blocking any single pathway is ineffective for many tumor types, including pancreatic, lung, and colorectal cancers.
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There are no FDA-approved upstream direct RAS prot...
There are no FDA-approved upstream direct RAS protein inhibitors currently available, except one that only acts on the specific V12C mutant sub-set. Qualigen and collaborators at the University of Louisville are characterizing RAS-RAL interactions and developing a series of highly potent compounds to take forward in preclinical development. Legacy drugs that target RAS signaling downstream demonstrate minimal clinical activity.
RAS Protein Inhibitors as Treatments for Advanced Solid Tumors
RAS is the most common cancer oncogene, present in one quarter of all cancers. Activating mutations in one of the three human RAS gene isoforms (KRAS, HRAS, or NRAS) are present in about one-fourth of all cancers. For example, mutant KRAS is found in 98% of pancreatic ductal adenocarcinomas, 52% of colon cancers, and 32% of lung adenocarcinomas. Just for these three cancer types alone, that means that cancers with mutant KRAS are diagnosed in more than 170,000 people each year in the US and cause more than 120,000 deaths. Novel mechanisms of action are desperately needed to address limitations in current standard of care for these deadly cancers.
Much of the data presented was generated from Qualigen’s collaborators in Geoff Clark’s lab at the University of Louisville RAS-F compounds demonstrate in-vitro and in-vivo activity in a variety of cell lines and xenograft models, including pancreatic, lung, and nerve sheath tumors. Lead RAS-F compounds have demonstrated inhibition in RAS-mutant cancer cell lines, including A549 (K12S/lung), CaoV3 (NF1/ ovarian), S462.TY (NF1/malignant peripheral nerve sheath tumors), HTB-185 (DAB2IP deficient/ medulloblastoma), and Mia-Paca-2 (K12C/pancreatic), with the latter having low nM IC50s. RAS-F compounds exhibit remarkable in-vivo anti-tumor activity in mouse xenograft models expressing lung cancer cell line RAS-K12V and pancreatic cancer cell line MiaPaca-2. Likewise, RAS compounds potentially enhances immune checkpoint therapy as illustrated in a syngeneic tumor graft using RAS-driven KPC cells. Mice from these studies exhibited normal weight gain as compared with controls.
Potential Advantages
- Composition of matter IP protection covering RAS-F portfolio
- RAS compounds inhibit cell growth across range of cell lines, including RAS mutants
- Low nanomolar IC50s in MiaPaca-2 cell line
- RAS compounds exhibits dose-sensitive effect on RAS/RAF complex in MiaPaca-2 cells
- Remarkable in-vivo anti-tumor activity in RAS-expressed mouse xenograft models
- Potential synergy with immune checkpoint therapies
- No serious adverse effects or weight differentiation with controls observed in mice
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