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

Abstract

Through specific structural modification of a 4-phenylindoline precursor, new 4-arylindolines containing a thiazole moiety were developed and found to be promising modulators of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis. Compound A30 exhibited outstanding biochemical activity, with an IC50 of 11.2 nM in a homogeneous time-resolved fluorescence assay. In the cell-based assay, A30 significantly promoted IFN-γ secretion and rescued T-cell proliferation, which were inhibited by PD-1 activation. Furthermore, A30 showed favorable in vivo antitumor activity in a mouse 4T1 breast carcinoma model. Moreover, in mouse CT26 colon carcinoma models, A30 potently suppressed the growth of CT26/PD-L1 tumor but did not obviously affect the growth of CT26/vector tumor. The results of flow cytometry analysis indicated that A30 inhibited tumor growth by activating the immune microenvironment. We concluded that A30 is a new starting point for further development of PD-1/PD-L1 interaction inhibitors as antitumor agents.

Design, Synthesis, and Pharmacological Evaluation of Biaryl-Containing PD-1/PD-L1 Interaction Inhibitors Bearing a Unique Difluoromethyleneoxy Linkage

“…As shown in Table , by incorporating the difluoromethyleneoxy motif as an unusual bioisosteric replacement of the methoxy linkage and retaining other structural components intact, compound 25 displayed an IC 50 of 31.87 nM against the PD-1/PD-L1 interaction, which is slightly more potent than reference compound 2 (IC 50 = 48.2 nM). A quick screening of a small set of alkylamino alcohols/acids widely used in the literature ,,− as the solvent interaction structural motif indicated that all the resulting compounds 26–28 retained high inhibitory activity against the PD-1/PD-L1 interaction, and compound 28 bearing a 2-amino-2-methylpropane-1,3-diol component showed more increased potency with an IC 50 value of 16.31 nM. Keeping the 2-amino-2-methylpropane-1,3-diol component intact and changing the substitution pattern of the central tetra-substituted phenyl ring from 3-methyl to the 4-chloro pattern led to compound 29 , showing a much improved potency with an IC 50 value of 5.93 nM.…”

“…18 A ring fusion strategy was conducted by Gong's and Wang's groups, and the representative compounds [1, 2,4]triazolo [4,3-α]pyridine 4 and indolin 5 showed IC 50 values of 92.3 and 11.2 nM, respectively. 19,20 More recently, Lai and co-workers reported a series of nitrophenyl derivatives, and compound 6 showed an IC 50…”

“…By taking advantage of the interaction profile of the biaryl core component, Hu and Holak reported a series of C 2 -symmetric 2,2′-dimethyl-3,3′-bis­(aryloxymethyl)-1,1′-biphenyl analogues, among which compound 3 (Figure ) exhibited an IC 50 value of 3.0 nM in the HTRF assay . A ring fusion strategy was conducted by Gong’s and Wang’s groups, and the representative compounds [1,2,4]­triazolo­[4,3-α]­pyridine 4 and indolin 5 showed IC 50 values of 92.3 and 11.2 nM, respectively. , More recently, Lai and co-workers reported a series of nitrophenyl derivatives, and compound 6 showed an IC 50 value of 2.7 nM . In addition, optimization of the methoxy (−CH 2 O−) linker was conducted by two groups.…”

PD-L1 Inhibitors: Different Classes, Activities, and Mechanisms of Action

“…Most of this work features the SAR analysis of biphenyl-cored molecules discovered by Bristol Myers Squibb. Although some new ideas such as symmetric molecules [21,22], terphenyls [17,18], or indolines [41] were proposed, only a moderate improvement of the bioactivity of the molecules could be achieved. It seems that the structure optimization of small molecules relying only on protein-based assays, such as the HTRF, is insufficient since many compounds present IC 50 values close to the lower limit of determination, but without a clear translation to the biological activity in a more complex, cellular environment.…”

Pyridine vs DABCO vs TBAB in Annulations of δ-Acetoxy Allenoates with Thioamides Leading to Dihydrothiophene, Thiopyran, and Thiazole Scaffolds

“…Thus, in continuation of our studies on allene chemistry, ,,,, herein we report stereo- and chemoselective annulations of δ-acetoxy allenoates with thioamides (Scheme e) that include (i) pyridine catalyzed [3 + 2] annulation via pyridinium ylide affording a novel class of dihydro-thiophene motifs as essentially single diastereomers , (ii) DABCO catalyzed [3 + 3] annulation delivering thiopyrans via 6-exo-dig cyclization, and (iii) tetra- n -butyl ammonium bromide (TBAB) catalyzed [3 + 2] annulation leading to thiazole cores with excellent stereoselectivity via 5-exo-trig cyclization, in which thioamide acts as sulfur and nitrogen donor. Dihydrothiophene, thiopyran, and thiazole motifs do have significant applications in medicinal chemistry …”