First-in-Class RNA Degrader Targets Historically ‘Undruggable’ MYC in Preclinical Multiple Myeloma Models

A first-in-class small-molecule RNA degrader showed antimyeloma activity in preclinical models by targeting and degrading MYC messenger RNA (mRNA), offering a potential new way to address a key driver of multiple myeloma (MM) that has long been difficult to target directly, according to findings published in Blood.¹

Rather than attempting to bind directly to the structurally disordered MYC protein, investigators developed MYC-RiboTAC, a ribonuclease-targeting chimera designed to recognize MYC mRNA and recruit the endogenous enzyme RNase L to destroy it. Across MM cell lines, primary patient samples, and 2 xenograft mouse models, the approach reduced MYC mRNA and protein expression, disrupted MYC-dependent transcriptional programs, and suppressed myeloma cell survival.¹

The findings are particularly notable because MYC dysregulation has long been implicated in MM progression, proliferation, metabolism, survival, and treatment resistance, yet direct pharmacologic inhibition of the protein has remained challenging.¹˒²

Targeting MYC Before the Protein Is Produced

MYC is a transcription factor that regulates numerous genes involved in cellular growth and survival. Genomic analyses have demonstrated that dysregulation of MYC and related signaling pathways is widespread in newly diagnosed MM, and MYC structural abnormalities are associated with disease progression from precursor plasma cell disorders toward overt malignancy.²

Despite its importance, MYC has historically been considered difficult to target directly because the protein is intrinsically disordered and lacks the well-defined binding pockets that conventional small-molecule drugs typically exploit.¹

MYC-RiboTAC attempts to bypass that obstacle altogether.

The heterobifunctional molecule contains one component that recognizes the internal ribosome entry site (IRES) within MYC mRNA and another that recruits RNase L, an endogenous ribonuclease capable of cleaving RNA.¹ Once brought into proximity with MYC mRNA, RNase L facilitates degradation of the transcript, reducing the amount of MYC protein that can subsequently be produced.

Previous research has demonstrated the feasibility of this broader RiboTAC strategy, in which small molecules are programmed to recognize structured regions of RNA and recruit RNase L to selectively eliminate disease-associated transcripts.³ The new study extends that concept specifically into MM and evaluates whether degradation of MYC mRNA can translate into meaningful antimyeloma activity.¹

MYC-RiboTAC Suppresses Myeloma Despite Bone Marrow Protection

Investigators assessed MYC-RiboTAC across MM cell lines and primary patient-derived samples with differing levels of MYC and RNase L expression. Treatment reduced MYC mRNA and protein in an RNase L–dependent manner and selectively suppressed transcriptional programs controlled by MYC.¹

Importantly, the compound inhibited growth in myeloma cells coexpressing MYC and RNase L even in the presence of the protective bone marrow microenvironment.¹

This is a potentially important preclinical finding because the bone marrow microenvironment provides survival signals that can protect malignant plasma cells and contribute to drug resistance. The persistence of MYC-RiboTAC activity under these conditions suggests that RNA degradation may remain effective despite at least some of the microenvironmental support available to MM cells.¹

Earlier research has also demonstrated the importance of MYC translation itself in myeloma biology. In experimental models, disruption of cap-independent MYC translation through its IRES reduced MYC expression and impaired myeloma growth, supporting this region of MYC mRNA as a therapeutically relevant vulnerability.⁴

Existing Myeloma Therapies May Strengthen RNA-Degrader Activity

One of the most clinically intriguing findings involved MYC-RiboTAC combinations with established MM therapies.

Investigators reported synergistic antimyeloma activity when MYC-RiboTAC was combined with the proteasome inhibitor carfilzomib and the immunomodulatory agents lenalidomide and pomalidomide.¹

The interaction may extend beyond simply combining drugs with different mechanisms. The researchers found that clinically active MM therapies could increase RNase L expression, potentially increasing the cellular machinery available for MYC-RiboTAC–mediated RNA degradation.¹

This raises the possibility that existing MM therapies could help create a more favorable intracellular environment for RNA-degrading agents, including in cells with lower baseline RNase L expression.

If confirmed in additional studies, the finding could have implications for future combination strategies. Rather than replacing established therapies, RNA degraders targeting MYC might eventually be explored as complementary agents capable of exploiting a molecular vulnerability that current regimens do not directly address.

Antitumor Activity Extends to In Vivo Models

MYC-RiboTAC also demonstrated antitumor activity in vivo.

In NOD SCID mice bearing MM xenografts, treatment significantly suppressed tumor growth across 2 separate models while demonstrating favorable pharmacokinetic and safety profiles.¹ Investigators additionally observed reductions in MYC protein within treated tumors, supporting the intended mechanism of action.

These results build upon earlier preclinical work with MYC-RiboTAC, in which investigators reported substantial tumor growth suppression in a myeloma xenograft model without overt toxicity.⁵

Taken together, the cell-based, patient-sample, and animal findings provide proof of concept that selective degradation of MYC mRNA can translate into antimyeloma activity across multiple experimental systems.

RNA Degradation Could Expand the Range of Drug-Targetable Cancer Drivers

The broader significance of the study may extend beyond MYC or MM.

Traditional targeted therapies generally depend on finding a druggable feature on the disease-driving protein itself. RiboTACs instead shift the therapeutic target upstream to RNA, potentially allowing investigators to intervene against oncogenic proteins whose physical structures make conventional inhibition difficult.³

That strategy is particularly compelling for MYC because MYC signaling plays a central role across numerous malignancies but has remained resistant to traditional direct-targeting approaches.

However, MYC-RiboTAC remains preclinical, and substantial questions must be addressed before the approach could be considered for patients. The findings do not establish clinical efficacy or safety, and additional studies will be required to determine optimal dosing, selectivity, long-term toxicity, potential resistance mechanisms, and whether adequate drug exposure can be achieved in humans.¹

Patient selection may also become important. Because the compound's activity depends on both MYC and RNase L, future development could require biomarkers identifying tumors most likely to respond or strategies that increase RNase L activity in tumors with insufficient baseline expression.

Nevertheless, the study provides a potentially important proof of concept for MM drug development: rather than continuing to search for a conventional way to bind an elusive oncogenic protein, directly destroying the RNA instructions used to produce it may offer another path forward.

REFERENCES

1. Maisano D, Wang T, Kulp SB, et al. A first-in-class RNA degrader reduces c-MYC expression and myeloma cell survival in preclinical models. Blood. Published online July 29, 2026. doi:10.1182/blood.2026033241

2. Misund K, Keane N, Stein CK, et al. MYC dysregulation in the progression of multiple myeloma. Leukemia. 2020;34(1):322-326. doi:10.1038/s41375-019-0543-4

3. Tong Y, Lee Y, Liu X, et al. Programming inactive RNA-binding small molecules into bioactive degraders. Nature. 2023;618(7963):169-179. doi:10.1038/s41586-023-06091-8

4. Shi Y, Sun F, Cheng Y, et al. Critical Role for Cap-Independent c-MYC Translation in Progression of Multiple Myeloma. Mol Cancer Ther. 2022;21(4):502-510. doi:10.1158/1535-7163.MCT-21-0016

5. Domenico Maisano, Tenghui Wang, Yuquan Tong, et al. A Novel Ribonuclease Targeting Small Molecule RNA-Degrader (MYC-RiboTAC) Overcomes MYC Dependency in Multiple Myeloma. Blood2024; 144 (Supplement 1): 3268. doi: https://doi.org/10.1182/blood-2024-205528