molecules of the month

The Cleave Therapeutics p97 (VCP) inhibitor, CB-5083, was a Ph. I clinical candidate for cancer that was terminated due to vision side effects including causing patients to see unusual colors (dyschromatopsia). In this paper, the authors suggest that the visual impairment was due to the compounds inhibition of the phosphodiesterase-6 (PDE6), which is involved in photoreceptor signal transduction. Fortunately, the effect on vision appears to be reversible, and the authors suggest CB-5083 should be re-evaluated in the clinic. This work suggests that PDE6 should be a more routinely screened against off-target, and preclinical ERG recordings can be used to assess functional safety relevance for compounds with in vitro PDE6 signals.