Cdk2as has activation defects in untreated cells, leading to lower abundance of Cdk2/cyclin A complexes and impaired R-point control. From this partially active state, Cdk2as can be turned ON or OFF, respectively, with the small molecules 6-BAP or 3-MB-PP1—both of which correct conformation, but with opposite effects on catalytic activity—to uncover a rate-limiting role of Cdk2 in pocket protein phosphorylation, R-point passage and S-phase entry.