In the next step, we evaluated the ability of PHOTACs 11-13 to degrade HDAC6 using PROTAC A6 as positive control. To this end, we treated MM.1S cells with 1 µM of 11-13 or A6 for 6 hours. The MM.1S cell line was selected due to its well-established use in PROTAC characterization and our prior findings demonstrating A6's high degradation activity in these cells. The experiments were conducted in two treatment groups. Both treatment groups were first treated with light of 505 nm to ensure full conversion into the trans-state. Next, one group was kept in the dark, and the second group was treated with light of 390 nm to switch the PHOTACs into the cis-state (see Supporting Information for experimental details; the results are summarized in Figure ). The positive control A6 achieved significant HDAC6 degradation after treatment with 390 and 505 nm. PHOTAC 11 induced HDAC6 degradation after irradiation with both wavelengths, likely due to its relatively long and flexible linker. The linker-less PHOTAC 13 failed to degrade HDAC6 in both treatment groups. In contrast, PHOTAC 12 with a relatively short γ-aminobutyric acid linker was unable to degrade HDAC6 after irradiation with 505 nm (<10% Dmax) but showed a pronounced and significant degradation of HDAC6 with a Dmax of ~50% at 1 µM concentration upon irradiation with light of 390 nm. These results indicate that the cis-state of PHOTAC 12 is an active degrader, while the trans-state is nearly inactive (<10% Dmax). Subsequently, we analyzed the HDAC degradation selectivity profile of 12 after activation to its cis-state by irradiation with light of 390 nm. Consistent with its parent PROTAC A6, activated PHOTAC 12 selectively degraded HDAC6 while causing minimal degradation of HDAC1, HDAC3, and HDAC8 (Figure ). Similarly, when preirradiated with 505 nm to ensure the trans-form, PHOTAC 12 did not induce degradation of HDAC1, HDAC3, or HDAC8 (Figure , Supporting Information). After confirming that 12 can be activated by treatment with light of 390 nm into an active and selective HDAC6 degrader, we analyzed the concentration dependency of 12-mediated HDAC6 degradation. To this end, we treated MM.1S cells with varying concentrations of 12 (0.123, 0.37, 1.11, 3.33, and 10 µM) and determined the resulting HDAC6 protein levels by immunoblot analysis. The maximum degradation was observed at a concentration of 0.37 µM and the HDAC6 protein levels remained stable up to the highest tested concentration (see Figure , Supporting Information).