Discovery of the programmed cell death-1/programmed cell death-ligand 1 interaction inhibitors bearing an indoline scaffold

Discovery of 4-Arylindolines Containing a Thiazole Moiety as Potential Antitumor Agents Inhibiting the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction

“…Structural optimizations on 1 were performed to identify compounds with superior activity in inhibition of the PD-1/PD-L1 interaction. In our previous study, the modification of the central phenyl ring of 1 failed to improve inhibitor activity . We speculated that the six-membered aromatic ring in this region might be replaced, and thus, we tried to increase the activity of inhibitors by introducing a five-membered heterocyclic fragment.…”

“…The amidation of 4-phenylindoline ( 7a ) with the commercially available 5-formylthiophene-2-carboxylic acid provided intermediate 8 . A NaBH 3 CN-promoted reductive amination reaction was used to convert 8 to compounds A1 and A2 . , Parallelly, intermediate 9 was obtained from 7 using a synthetic method similar to the preparation of 8 . The conversion of intermediate 9 to 11 was achieved via a two-step reaction comprising Stille coupling with tributyl­(vinyl)­stannane and olefin oxidization by NaIO 4 in the presence of K 2 OsO 4 ·2H 2 O. , Finally, the desired compounds, A5 and A6 , were synthesized from 11 under conditions similar to those described for preparing A1 .…”

“…In our previous study, we reported a 4-phenylindoline-containing compound, 1 , as an inhibitor of the PD-1/PD-L1 interaction . Remarkably, 1 exhibited excellent efficacy in restoring T-cell function, which was suppressed by PD-1 activation, and this was significantly superior to that of BMS-1.…”

Optochemical Control of Immune Checkpoint Blockade via Light‐Triggered PD‐L1 Dimerization

“…From structure–activity relationships (SARs) studies, the tail group of BMS is required to form hydrogen bonds with PD‐L1 to keep its pharmacological activity. [ 22,23 ] Therefore, modifying the tail group is a feasible way to cage the activity of the inhibitor. DEACM was chosen as the PPG due to its fast photocleavable ability by visible light irradiation ( λ > 400 nm) without producing toxic byproducts and good biocompatibility.…”

“…With light irradiation at 420 nm, DEACM was removed to release BMS‐1, [ 20 ] which successfully blocked PD‐1/PD‐L1 interaction and triggered the release of cytokines from Jurkat T cells. [ 21–23 ] The study demonstrated the first example of precisely controlling PD‐1/PD‐L1 interaction with light, paving the way to targeted and controlled immune checkpoint blockade for cancer therapy.…”