Matthew Disney, Founder and Director of Ribonaut Therapeutics, Institute Professor at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, shared on LinkedIn:
“MYC has long been considered ‘undruggable.’ Instead of trying to drug the protein, we went after its RNA. This is part of our long standing protein of viewing small molecule druggabilty of genetically defined targets at the level of mRNA.
This work is part of our long-standing effort to expand the druggability of genetically defined disease targets by targeting their messenger RNAs with small molecules.
I am excited to share an important paper in Blood arising from our long-term collaboration with Nikhil C. Munshi, Eugenio Morelli, first author Domenico Maisano, Chungen Li, Tenghui Wang, Mehmet Kemal Samur, Yuquan Tong, Jessica Disney, Michael Cameron, and many others.
This study establishes a comprehensive preclinical package for MYC-RiboTAC, a small-molecule RNA degrader that binds the MYC IRES and recruits RNase L to degrade MYC mRNA. MYC-RiboTAC reduces MYC RNA and protein, suppresses MYC-driven transcriptional programs, kills multiple myeloma cells, remains active within the protective bone marrow microenvironment, and demonstrates significant antitumor activity in two of the most important preclinical mouse models of multiple myeloma. It also shows favorable pharmacokinetic and safety profiles.
One of the most important findings is that FDA-approved multiple myeloma therapies can increase RNase L expression – even in cells with little or no detectable RNase L at baseline – and enhance the activity of MYC-RiboTAC. This suggests that existing medicines may do more than simply combine with an RNA degrader: they may induce the cellular machinery needed to enable RNA degradation.
This work provides strong evidence that disease-driving mRNAs encoding historically ‘undruggable’ proteins can be directly targeted and degraded with small molecules.
Congratulations to the entire collaborative team.”
Title: A first-in-class RNA degrader reduces c-MYC expression and myeloma cell survival in preclinical models
Authors: Domenico Maisano, Tenghui Wang, Steffen Benham Kulp, Vanessa Katia Favasuli, Yuquan Tong, Michela Cumerlato, Chungen Li, Francesca Barello, Marcello Turi, Paola Rampa, Rosa Alba Parisi, Filip Garbicz, Francesco Ladisa, Giulia Giorgetti, Chandraditya Chakraborty, Laure Vreux, Valentina Sangiorgio, Ivana Sarotto, Anil Aktas Samur, Mehmet K. Samur, Ruben D. Carrasco, Mariateresa Fulciniti, Michael D. Cameron, Kenneth C. Anderson, Annamaria Gulla, Jessica Childs-Disney, Matthew D. Disney, Eugenio Morelli, Nikhil C. Munshi
Read the paper
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