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

Area of Science:

• Oncology
• Molecular Biology
• RNA Therapeutics

Background:

• The c-MYC (MYC) oncogene drives multiple myeloma (MM), but its structural disorder makes direct protein targeting difficult.
• Current therapeutic strategies for MM often face challenges in effectively targeting MYC.

Purpose of the Study:

• To evaluate the biological activity and molecular mechanism of a novel MYC mRNA-targeting chimera (MYC-RiboTAC).
• To assess the potential of MYC-RiboTAC as a precision cancer therapy for multiple myeloma.

Main Methods:

• Developed a heterobifunctional molecule (MYC-RiboTAC) targeting the MYC internal ribosomal entry site (IRES) and recruiting RNase L.
• Tested MYC-RiboTAC in primary patient MM samples, MM cell lines, and in vivo MM xenograft models.
• Assessed MYC mRNA and protein levels, transcriptional programs, cell growth inhibition, drug synergy, and pharmacokinetic/safety profiles.

Main Results:

• MYC-RiboTAC reduced MYC mRNA and protein levels in an RNase L-dependent manner.
• Demonstrated potent anti-MM activity, suppressing cell growth and MYC-driven transcription, even in protective bone marrow environments.
• Showed synergy with existing MM therapies and favorable safety/pharmacokinetic profiles in preclinical models, significantly suppressing tumor growth.

Conclusions:

• RNA degraders, like MYC-RiboTAC, can effectively target mRNAs encoding "undruggable" proteins such as MYC.
• MYC-RiboTAC represents a promising new therapeutic strategy for precision cancer therapy in multiple myeloma.