ideasIdea
Turn a brake back on: drugs that reactivate the PP2A phosphatase
Cells have an enzyme, PP2A, that removes the growth signals cancer relies on. Cancers switch it off. Drugs that switch it back on are an unusual and largely untried approach.
PP2A is a tumour suppressor phosphatase inactivated in many cancers through SET, CIP2A or subunit mutations. Small-molecule activators of PP2A (SMAPs) and the related class of phosphatase-directed compounds destabilise MYC and other oncoproteins by promoting their dephosphorylation and degradation. Activating an enzyme is harder than inhibiting one, which is why the class is underdeveloped.
Hypothesis
PP2A activation lowers MYC protein levels in tumours in vivo and synergises with MEK or CDK4/6 inhibition to produce durable regressions in models where either agent alone fails.
Rationale
Phosphatase activation attacks the stability of undruggable oncoproteins indirectly; MYC's short half-life makes it especially sensitive to dephosphorylation at the residue that protects it from degradation.
What would test it
In vivo pharmacodynamics of a tool SMAP in KRAS-driven lung models, with MYC protein and phospho-site readouts, and a combination matrix with MEK inhibition.
Maturity
preclinical evidence
Who has to act
research
Cost to try
Medium ($1M to $50M)
Years to first evidence
7
Bottlenecks it attacks
- The undruggable drivers · The proteins that drive most cancers, such as MYC, mutant p53 and most RAS variants, still have no good drug.