A first-in-class RNA degrader reduces c-MYC expression and myeloma cell survival in preclinical models.

The c-MYC (MYC) oncogene is a critical driver of multiple myeloma (MM), however, direct targeting of the MYC protein has proven challenging due to its intrinsic structural disorder. In this study, we evaluated the biological activity and molecular mechanism of a ribonuclease-targeting chimera (RiboTAC) designed to promote the degradation of MYC mRNA (MYC-RiboTAC) across a panel of primary patient MM samples and MM cell lines. This heterobifunctional molecule consists of a small molecule targeting the MYC internal ribosomal entry site (IRES) conjugated to a small-molecule recruiter of endogenous RNaseL. The MYC-RiboTAC reduces MYC mRNA and protein levels in an RNase L-dependent manner, selectively inhibits MYC-driven transcriptional programs, and exhibits potent anti-MM activity. It effectively suppresses cell growth in MM cells co-expressing MYC and RNase L, even in the presence of the protective bone marrow. Furthermore, it synergizes with clinically active agents such as carfilzomib, lenalidomide, and pomalidomide. Importantly, MYC-RiboTAC displays favorable safety and pharmacokinetic profiles in mice and significantly suppresses tumor growth in NOD SCID mice bearing MM xenografts, as shown in two different models. These findings highlight the potential of RNA degraders to target mRNAs encoding "undruggable" proteins such as MYC, offering a promising avenue for precision cancer therapy.