Direct Upstream Inhibition of RAS Oncoproteins

Our RAS 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 RAL 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. There is only one FDA approved therapy for the treatment of KRAS G12C-mutated locally advanced or metastatic. 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 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 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 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 enhance 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 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
Posters & Publications
- Poster – AACR Special Conference: Targeting RAS, March 2023
A Novel RAS inhibitor for Luminal B and Triple Negative Breast Cancers - Poster – AACR Special Conference: Targeting RAS, March 2023
A Novel RAS inhibitor for Pancreatic Cancer - Poster – The Fourth RAS Initiative Symposium 2022
A novel pan-RAS inhibitor for Malignant Peripheral Nerve Sheath Tumors (Authors: Tariq Arshad, Geoff Clark) - Poster – The Fourth RAS Initiative Symposium 2022
A Novel RAS inhibitor for Pancreatic Cancer (Authors: Tariq Arshad, Geoff Clark) - Abstract – ASCO Annual Meeting, June 2022
A Novel RAS Inhibitor for Pancreatic Ductal Adenocarcinoma (Authors: Tariq Arshad, Geoff Clark) - Abstract – ASCO Annual Meeting, June 2022
A Novel Pan-RAS Inhibitor for Malignant Peripheral Nerve Sheath Tumors (Authors: Tariq Arshad, Geoff Clark) - Research Article – Molecular and Cellular Biology (journals.asm.org), December 2020
p75-Ras-GRF1 Is a c-Jun/AP-1 Target Protein: Its Up Regulation Results in Increased Ras Activity and Is Necessary for c-Jun-Induced Nonadherent Growth of Rat1a Cells - Research Article – Journal of Thoracic Disease (jtd.amegroups.com), May 2019
The role of RASSF proteins in modulating RAS driven lung tumors in vivo - Poster – Novel RAS inhibitors for NF1 disease – 2019
- Research Article – Cancer Research (cancerres.aacrjournals.org), May 2018
RASSF1A Deficiency Enhances RAS-Driven Lung Tumorigenesis - Research Article – BMC Cancer (bmccancer.biomedcentral.com), April 2018
Micro-RNA-186-5p inhibition attenuates proliferation, anchorage independent growth and invasion in metastatic prostate cancer cells - Research Article – Cancer Letters (sciencedirect.com), April 2017
The Role of the NORE1A Tumor Suppressor in Oncogene Induced Senescence - Research Article – Hepatology (aasldpubs.onlinelibrary.wiley.com), January 2017
NS5B Promotes Degradation of the NORE1A Tumor Suppressor to Facilitate Hepatitis C Virus Replication - Research Article – Seminars in Cell & Developmental Biology (sciencedirect.com), June 2016
Ras signaling through RASSF proteins - Research Article – Molecular & Cellular Oncology (tandfonline.com), April 2016
Nore1a drives Ras to flick the P53 senescence switch - Research Article – Cancers (mdpi.com), March 2016
NORE1A Regulates MDM2 Via β-TrCP - Research Article – Oncotarget (oncotarget.com), March 2016
Rheb may complex with RASSF1A to coordinate Hippo and TOR signaling - Research Article – Journal of Biological Chemistry (jbc.org), December 2015
Ras Regulates Rb via NORE1A - Research Article – Frontiers in Genetics (frontiersin.org), August 2015
A porcine model system of BRCA1 driven breast cancer - Research Article – Journal of Cell Biology (rupress.org), March 2015
NORE1A is a Ras senescence effector that controls the apoptotic/senescent balance of p53 via HIPK2