MYC
MYC is the most commonly amplified cancer gene, a master switch that turns on thousands of growth genes. It has no pocket for a conventional drug, so it remained 'undruggable' for 40 years; the first direct MYC drugs finally entered trials in the 2020s.
MYC family transcription factors (MYC, MYCN, MYCL) dimerise with MAX to drive ribosome biogenesis, metabolism, and proliferation; deregulated in >50% of cancers via amplification, translocation (Burkitt), or upstream signalling (Wnt, RAS, Notch). MYC also suppresses immune recognition (CD47, PD-L1). Direct approaches: OMO-103 (Omomyc mini-protein, phase 1/2 in PDAC), MYC degraders, and MAX-stabilising molecules; indirect: CDK9 and BET inhibitors that reduce MYC transcription, PLK1 and AURKA inhibitors that destabilise MYC/MYCN protein (neuroblastoma), and synthetic-lethal dependencies (mTOR, splicing).
In one picture
A conductor who can make every section of the orchestra play louder at once. You cannot take away the baton, so drugs try to silence the score (transcription), tire the conductor (degradation), or exploit the fact that a full-volume orchestra cannot afford a single missing player.
Diagram
top- OMO-103 (Omomyc) phase 1/2 in pancreatic cancer
- BET and CDK9 inhibitors reduce MYC transcription (haematologic trials)
- AURKA inhibitors in MYCN-amplified neuroblastoma
- MYC-driven dependencies: mTOR, spliceosome, glutamine
Notes
top- Leading programmes: Soucek (VHIO, Omomyc/Peptomyc); Felsher (Stanford, MYC addiction); Eilers (Würzburg); Dang (Ludwig); Bradner/Vakoc (CSHL, BET inhibitors).
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