Potential First-In-Class Pan-RAS Inhibitors Exhibit Efficacy in Variety of Difficult-To-Treat In Vivo Cancer Models

Qualigen is developing a platform of small molecule Pan-RAS oncogene protein-protein interaction inhibitors for treating adult and pediatric RAS-driven tumors with high unmet medical need. We are looking to leverage our compelling in vivo xenograft data to identify lead candidates for IND-enabling studies that address potential mechanisms of emerging KRAS G12C resistance through a pan-RAS approach.

RAS Pathway

Mechanistic Rationale for pan-RAS Inhibition

Figure 1
Qualigen is collaborating with Dr. Geoff Clark and Dr. Joe Burlison at the University of Louisville, Kentucky, under a multi-year Sponsored Research Agreement. Our research focus has been characterizing RAS-RAL interactions and developing a series of highly potent compounds to take forward into preclinical development. Our RAS portfolio includes a series of highly potent pan-RAS inhibitors based on an F3 scaffold that suppresses the interaction of endogenous RAS with c-RAF, and is able to influence the KRAS, HRAS, and NRAS effector pathways. RAS acts as a “hub” that activates multiple effector pathways, hence blocking any single pathway may be ineffective for many RAS-driven tumor types, including pancreatic, lung, and colorectal cancers. This approach potentially enables a differentiated, pan-RAS strategy for inhibiting the MAPK, PI3K, and TOR pathways implicated in cancer cell proliferation, survival, and differentiation (see Figure 1).

Pan-RAS Inhibitors as Treatments for Advanced Solid Tumors

RAS is the most common cancer oncogene, present in approximately a quarter or more of all cancers. Activating mutations in one of the three human RAS gene isoforms (KRAS, HRAS, or NRAS) are present in many tumor types, including 98% of pancreatic ductal adenocarcinomas, 52% of colon cancers, and 32% of lung adenocarcinomas. Cancers with mutant KRAS are diagnosed in more than 170,000 people each year in the US and cause more than 120,000 deaths for these three cancers alone. We believe novel mechanisms of action are desperately needed to address limitations in current standard of care such as chemotherapies like gemcitabine for treatment of these deadly cancers. In 2021, the FDA approved the first KRAS G12C targeted therapy, Sotorasib, under an accelerated approval for the treatment of KRAS G12C-mutated locally advanced or metastatic NSCLC (Non Small Cell Lung Cancer) in adult patients who have received at least one prior systemic therapy. However, emerging KRAS G12C resistance data affecting depth and duration of responses suggests a need for a pan-RAS approach that may address KRAS G12C resistance mechanisms.

Figure 1
Our pan-RAS inhibitors have demonstrated in-vitro and in-vivo activity in a variety of cell lines and xenograft models, including pancreatic, lung, and nerve sheath tumors. Likewise, RAS 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 with low uM IC50s. Likewise, our compounds exhibit remarkable in-vivo anti-tumor activity in mouse lung cancer xenograft models and pancreatic cancer cell line MiaPaca-2. Moreover, RAS compounds show potential synergy with PDL-1 immune checkpoint therapy in a syngeneic tumor graft using RAS-driven KPC cells. (Figure 2). Mice from these studies exhibited normal weight gain and similar liver enzyme levels as compared with controls.

Potential Advantages

  1. Inhibit KRAS G12C (MiaPaca-2) and KRAS G12D (Panc-1) at low micromolar concentrations
  2. Bind HRAS and NRAS in low micromolar concentrations
  3. Exhibit dose-sensitive effect on RAS/RAF complex in MiaPaca-2 cells
  4. Inhibit Wild-Type (WT) RAS-driven tumors in vivo
  5. Robust in-vivo anti-tumor activity in RAS-expressed mouse xenograft models
  6. Potential synergy with immune checkpoint therapy in vivo
  7. No serious adverse effects or weight differentiation with controls observed in mice at efficacious doses
  8. Composition of matter IP protection covering Qualigen’s RAS portfolio
  9. Potential to overcome lack of clinical durability with existing KRAS inhibitors by binding to RAS effector loop and overcoming resistance mechanisms associated with a single mutant isoform

Posters & Publications

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