Ribosome biogenesis (RiBi)

Ribosome biogenesis is the complex and highly energy-intensive cellular process of manufacturing ribosomes, the essential machineries for protein synthesis. This pathway involves the coordinated action of RNA polymerases I, II, and III, approximately 80 ribosomal proteins, and over 200 non-ribosomal assembly factors to synthesize, process, and assemble ribosomal RNA (rRNA) and proteins into functional subunits within the nucleolus. In malignant cells, ribosome biogenesis is frequently hyperactivated to sustain the high demand for protein synthesis required for unrestricted growth and proliferation, often driven by oncogenic signals such as MYC and mTORC1. Targeting this pathway has emerged as a potent therapeutic strategy in oncology, with a focus on inducing 'nucleolar stress' to trigger cell death or senescence. Small molecules like CX-5461 and BMH-21 selectively target the rate-limiting step of ribosome biogenesis by inhibiting RNA polymerase I transcription. This inhibition disrupts the nucleolar structure and releases ribosomal proteins that bind and inactivate MDM2, thereby stabilizing the p53 tumor suppressor and promoting apoptosis in cancer cells. Because cancer cells are often more dependent on high rates of ribosome production than normal cells, this approach offers a unique therapeutic window for treating various solid tumors and hematological malignancies.

Other names

Ribosome synthesisRibosome assemblyNucleolar ribosome biogenesisrRNA synthesis and processing

Inhibition of RNA polymerase I (Pol I) transcription of ribosomal DNA, interference with ribosomal RNA (rRNA) processing and maturation, and induction of the nucleolar stress response leading to p53 stabilization and subsequent cell cycle arrest or apoptosis.