In vitro and in vivo degradation of programmed cell death ligand 1 (PD-L1) by a proteolysis targeting chimera (PROTAC)

Wang, Yubo; Zhou, Yuanyuan; Cao, Sheng; Sun, Yue; Dong, Zhiqiang; Li, Chen; Wang, Haoran; Yao, Yuhong; Yu, Haiyan; Song, Xiangyi; Li, Ming; Wang, Jiefu; Wei, Mingming; Yang, Guang; Yang, Cheng

doi:10.1016/j.bioorg.2021.104833

Cited by 52 publications

(40 citation statements)

References 31 publications

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“…The PD-1/PD-L1 blockade induced by 4 and 5 was unrelated to the downregulation of PD-L1 expression in the PD-L1-expressing MDA-MB-231 cells. This is in clear contrast to previous reports which claimed PROTAC-like activity of similar pomalidomide/thalidomide-containing chimeras [ 26 , 27 ]. Of note, downregulation of PD-L1 expression was very limited in these studies and was only observed at considerably high concentrations (2.5–10 µM), which is unusual for successful PROTAC probes, which are known to be active in the pM–nM concentration range.…”

Section: Discussioncontrasting

confidence: 99%

“…Inspired by recent findings concerning the effect of pomalidomide on PD-L1 induction [ 25 ] and postulated activity of PD-L1-targeting PROTACs [ 26 , 27 ], we designed several PD-L1–linker–pomalidomide synthetic constructs based on our recently published PROTAC and PD-L1 work [ 24 , 28 ]. The syntheses of the proposed inhibitors are shown in Scheme 1 , Scheme 2 and Scheme 3 and comprise the known syntheses of the PD-L1 inhibitors BMS-1166 and BMS-202 [ 17 , 19 , 29 , 30 ], terphenyl [ 31 , 32 ] and imidazopyridines [ 24 ], which then were linked together with pomalidomide derivatives to form the desired chimeras.…”

Section: Resultsmentioning

confidence: 99%

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Biphenyl Ether Analogs Containing Pomalidomide as Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction

et al. 2022

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New biphenyl-based chimeric compounds containing pomalidomide were developed and evaluated for their activity to inhibit and degrade the programmed cell death-1/programmed cell death- ligand 1 (PD-1/PD-L1) complex. Most of the compounds displayed excellent inhibitory activity against PD-1/PD-L1, as assessed by the homogenous time-resolved fluorescence (HTRF) binding assay. Among them, compound 3 is one of the best with an IC50 value of 60 nM. Using an ex vivo PD-1/PD-L1 blockade cell line bioassay that expresses human PD-1 and PD-L1, we show that compounds 4 and 5 significantly restore the repressed immunity in this co-culture model. Western blot data, however, demonstrated that these anti-PD-L1/pomalidomide chimeras could not reduce the protein levels of PD-L1.

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Section: Discussioncontrasting

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Biphenyl Ether Analogs Containing Pomalidomide as Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction

et al. 2022

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“…Furthermore, they developed d9A-2, a pomalidomide-based PROTAC that degraded SLC family 9 member A1 (SLC9A1) — and, to a lesser extent, other SLC9 family members — leading to impaired pH homeostasis and cytotoxicity in multiple cancer cell lines, via a mechanism consistent with UPS-dependent TPD 52 . More recently, Wang et al 54 showed that programmed cell death ligand 1 (PDL1) — an immune checkpoint protein that resides on the cell surface to carry out its natural function but circulates between the surface and the cytoplasm — could be degraded using a CRBN-based PROTAC linked to the BMS-37 PDL1 warhead in MC-38 cells.…”

Section: Outlook For the Next 20 Years Of Tpdmentioning

confidence: 99%

PROTAC targeted protein degraders: the past is prologue

Békés

Langley

Crews

2022

Nat Rev Drug Discov

1,317

996

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Targeted protein degradation (TPD) is an emerging therapeutic modality with the potential to tackle disease-causing proteins that have historically been highly challenging to target with conventional small molecules. In the 20 years since the concept of a proteolysis-targeting chimera (PROTAC) molecule harnessing the ubiquitin–proteasome system to degrade a target protein was reported, TPD has moved from academia to industry, where numerous companies have disclosed programmes in preclinical and early clinical development. With clinical proof-of-concept for PROTAC molecules against two well-established cancer targets provided in 2020, the field is poised to pursue targets that were previously considered ‘undruggable’. In this Review, we summarize the first two decades of PROTAC discovery and assess the current landscape, with a focus on industry activity. We then discuss key areas for the future of TPD, including establishing the target classes for which TPD is most suitable, expanding the use of ubiquitin ligases to enable precision medicine and extending the modality beyond oncology.

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“…It is suggested that a linker with five or six carbon chains in length provides the most potent PROTAC molecules, which is in agreement with our previous findings. 22,23 Moreover, the amide bond connecting with the piperazine group of dovitinib was necessary to maintain the antileukemia activity. It is also demonstrated that pomalidomide was the best ligand of E3 ligase for the PROTAC modification of dovitinib since the replacement of pomalidomide by the VHL ligand (compound 28) led to significantly reduced antiproliferative effect against FLT3-ITD + AML cells when compared with compounds 1 and 2, which may be due to the decline in activity to induce the degradation of the FLT3-ITD protein in cells (Figure S1).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Proteolysis-Targeting Chimera (PROTAC) Modification of Dovitinib Enhances the Antiproliferative Effect against FLT3-ITD-Positive Acute Myeloid Leukemia Cells

Cao

Liu

et al. 2021

J. Med. Chem.

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Acute myeloid leukemia (AML) refers to one of the most lethal blood malignancies worldwide. FLT3-ITD mutation is recognized as the most common one that predicted a poorer prognosis. There have been many prominent FLT3-ITD inhibitors approved by the FDA for clinical therapies. However, as impacted by undesirable off-target effects, differentiated metabolic issues, and clinical drug resistance problems, it remains challenging to discover alternative and promising solutions for treating FLT3-ITD+ AML. In this study, dovitinib was chemically modified and converted into CRBN-recruiting PROTACs. Two active compounds were identified, which showed enhanced antiproliferative effects against FLT3-ITD+ AML cells, both in vitro and in vivo. As demonstrated from further biological evaluation, the compounds could induce the degradation of the FLT3-ITD and KIT proteins in a ubiquitin–proteasome-dependent manner and completely block their downstream signaling pathway. The findings of this study would provide another promising strategy to develop novel therapies for FLT3-ITD+ AML.

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In vitro and in vivo degradation of programmed cell death ligand 1 (PD-L1) by a proteolysis targeting chimera (PROTAC)

Cited by 52 publications

References 31 publications

Biphenyl Ether Analogs Containing Pomalidomide as Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction

Biphenyl Ether Analogs Containing Pomalidomide as Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction

PROTAC targeted protein degraders: the past is prologue

Proteolysis-Targeting Chimera (PROTAC) Modification of Dovitinib Enhances the Antiproliferative Effect against FLT3-ITD-Positive Acute Myeloid Leukemia Cells

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