On April 7, 2024 Ribometrix, a biotechnology company developing small molecule therapeutics that modulate RNA biology, reported the full data from two posters highlighting advancements across two distinct modalities presented at the 2024 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, held April 5-10 in San Diego, CA (Press release, Ribometrix, APR 7, 2024, View Source [SID1234641840]).
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The posters include the company’s first public disclosure of data validating its RNA-targeting platform for designing small molecules to bind directly to RNA; the ability of these small molecules to selectively bind mRNA encoding the important cancer driver c-MYC and reduce c-MYC protein expression; and data supporting the multi-tumor therapeutic potential of the company’s program targeting the RNA-binding protein eukaryotic translation initiation factor 4E (eIF4E).
Ribometrix’s RNA-targeting platform identifies small molecules that bind oncogene mRNA; proof-of-concept delivered via c-MYC program
These data support Ribometrix’s world-leading expertise in RNA structural analysis which informs its identification of novel small molecule binders of RNA intended to disrupt downstream protein translation.
The data in the first poster demonstrate how Ribometrix:
Identified druggable RNA structure motifs and used them to screen for RNA binders with properties comparable to approved protein-targeting drugs, suggesting the ability to leverage established small molecule development processes in future development.
Generated RNA-targeting compounds that directly engage c-MYC mRNA.
Selectively reduced c-MYC protein and downstream effectors in a c-MYC expressing cell line.
"For the first time, we are sharing data demonstrating our ability to directly target RNA with a small molecule and deliver a concomitant reduction in associated protein and downstream targets, the longtime scientific goal of our field," said Michael Solomon, Ph.D., Chief Executive Officer of Ribometrix. "Our ability to bind c-MYC mRNA and show functional consequence validates our platform and demonstrates the potential to use this approach to address other high-value targets that are currently intractable to traditional small molecule approaches."
Novel eIF4E inhibitors potently and selectively suppress tumor growth
These preclinical data are the most advanced-to-date demonstration that inhibiting RNA-binding protein (RBP) eIF4E can serve as a potential anti-cancer therapy. These data build on presentations at last year’s Society for Melanoma Research and San Antonio Breast Cancer Symposium. eIF4E is a main regulator and rate limiting factor for protein synthesis and is elevated in many kinds of tumors. These attributes make it a promising target for multiple hard-to-treat cancers as both an effector of several targeted therapy pathways and a key part of many resistance mechanisms. These roles create opportunities for combining eIF4E inhibition with standard-of-care (SOC) to improve efficacy and duration of response in treatment naive patients as well as restoring sensitivity to patients with resistance.
The data in the second poster demonstrate how Ribometrix:
Synergistically enhanced in vivo anti-tumor efficacy of SOC though combination with its eIF4E inhibitor across many tumor types including non-small cell lung cancer, breast cancer, and melanoma.
Caused tumor regression in mouse models of aggressive melanoma, ER+ breast cancer and non-small cell lung cancers through combination treatment with SOC.
Restored sensitivity to SOC in multiple resistant cell lines in vitro through combination with its eIF4E inhibitor, providing a potential mechanism for re-sensitizing resistant patient populations to initial lines of treatment.
"The ability to target RNA-binding proteins that regulate oncogenes is a powerful modality with the potential to address cancer indications with high unmet need. Our eIF4E inhibitor has demonstrated broad applicability to amplify the benefit of current therapies through enhancing the anti-tumor effects or reversing resistance," said Jessica Sorrentino, Ph.D., SVP of Translational Medicine. "We are making excellent progress towards our goal of filing an IND in the first half of 2025. Together with our c-MYC data, we are demonstrating multiple unique and innovative strategies that leverage our deep RNA expertise to tackle currently intractable targets with new RNA-directed modalities."
The posters are available to view on the "Publications" page of Ribometrix’s website.
About eIF4E
Eukaryotic translation initiation factor 4E (eIF4E) is a crucial regulatory component of mRNA translation and well-documented driver of oncogenesis. Clinically, eIF4E activity is elevated in many tumor indications and it is typically associated with poor prognosis. Targeting eIF4E has the potential to enhance anti-cancer activity when given in combination with standard-of-care. Additionally, eIF4E inhibition has the potential to overcome drug resistance and re-sensitize tumors to anti-cancer therapies. Based on substantial external and in-house data, Ribometrix is developing eIF4E inhibitors as a promising combination therapy approach and treatment for treatment-resistant tumors.
About c-MYC
c-MYC is a well-validated oncogene with broad anti-cancer potential, as c-MYC expression is dysregulated in more than 70% of cancers and a key regulator in nearly every aspect of the oncogenic process. c-MYC has remained intractable to traditional small molecule drug discovery, primarily due to its lack of a defined small molecule binding pocket. By targeting the c-MYC mRNA with small molecules, Ribometrix is bypassing the "undruggable" challenges to successfully reduce c-MYC protein levels and develop a novel anti-cancer therapeutic for c-MYC-driven cancers.