Discovery and characterization of novel potent BCR-ABL degraders by conjugating allosteric inhibitor

Liu, Haixia; Mi, Qianglong; Ding, Xinyu; Lin, Chencen; Liu, Linyi; Ren, Chaowei; Shen, ShuTing; Shao, Yubao; Chen, Jinju; Zhou, Yongqi; Ji, Liting; Zhang, Heqiao; Bai, Fang; Yang, Xiaobao; Yin, Qianqian; Jiang, Biao

doi:10.1016/j.ejmech.2022.114810

Cited by 18 publications

(17 citation statements)

References 61 publications

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“…Since then, a series of novel and highly effective VHL E3 ligase ligands have been discovered and reported, typified by compounds VHL‐1–VHL‐8 (Figure 2) with improved lipophilicity 119,120,122 . The studies on the eutectic structure of the VHL ligand with the protein helps to locate the solvent‐exposed region, leading to revelation of four possible linking sites without negatively affecting the interaction between the protein and the corresponding ligand (Figure 2; PDB ID: 4W9H) 123–134 . These sites are (a) terminal amino; (b) sulfhydryl; (c) benzyl; and (d) phenolic hydroxyl group on the benzene ring 113,135–141 .…”

Section: Vhl Ligands and Their Utilizations In Protacs For Cancer Dru...mentioning

confidence: 99%

“… 119 , 120 , 122 The studies on the eutectic structure of the VHL ligand with the protein helps to locate the solvent‐exposed region, leading to revelation of four possible linking sites without negatively affecting the interaction between the protein and the corresponding ligand (Figure 2 ; PDB ID: 4W9H). 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 These sites are (a) terminal amino; (b) sulfhydryl; (c) benzyl; and (d) phenolic hydroxyl group on the benzene ring. 113 , 135 , 136 , 137 , 138 , 139 , 140 , 141 At present, VHL E3 ligand has been widely and successfully applied in the design and synthesis of PROTAC as one of the most commonly used E3 ligands (Table 1 ).…”

Section: Vhl Ligands and Their Utilizations In Protacs For Cancer Dru...mentioning

confidence: 99%

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PROTACs: A novel strategy for cancer drug discovery and development

Han

Sun

2023

MedComm

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Proteolysis targeting chimera (PROTAC) technology has become a powerful strategy in drug discovery, especially for undruggable targets/proteins. A typical PROTAC degrader consists of three components: a small molecule that binds to a target protein, an E3 ligase ligand (consisting of an E3 ligase and its small molecule recruiter), and a chemical linker that hooks first two components together. In the past 20 years, we have witnessed advancement of multiple PRO-TAC degraders into the clinical trials for anticancer therapies. However, one of the major challenges of PROTAC technology is that only very limited number of E3 ligase recruiters are currently available as E3 ligand for targeted protein degradation (TPD), although human genome encodes more than 600 E3 ligases. Thus, there is an urgent need to identify additional effective E3 ligase recruiters for TPD applications. In this review, we summarized the existing RING-type E3 ubiquitin ligase and their small molecule recruiters that act as effective E3 ligands of PRO-TAC degraders and their application in anticancer drug discovery. We believe that this review could serve as a reference in future development of efficient E3 ligands of PROTAC technology for cancer drug discovery and development.

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Section: Vhl Ligands and Their Utilizations In Protacs For Cancer Dru...mentioning

confidence: 99%

Section: Vhl Ligands and Their Utilizations In Protacs For Cancer Dru...mentioning

confidence: 99%

PROTACs: A novel strategy for cancer drug discovery and development

Han

Sun

2023

MedComm

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“…Therefore, effective degradation of BCR-ABL could address the issues on TKI resistance and leukemia-initiating cells (LICs), and PROTAC-based protein degradation strategy may represent a new therapeutic approach (Bekes et al, 2022). Currently, based on different ubiquitin E3 ligases, including VHL, CRBN and IAP, PROTAC-based degraders at nM level have shown significant degradation of BCR-ABL in CML cell lines, cell lines carrying mutations in BCR-ABL as well as patient-derived primary cells containing multiple BCR-ABL mutations ( Demizu et al, 2016; Lai et al, 2016; Shimokawa et al, 2017; Zhao et al, 2019; Burslem et al, 2019; Liu et al, 2022). Unfortunately, the excellent cellular activity by the PROTAC-based degraders has not been able to translate to in vivo efficacy, even in rare examples of xenografted mouse models ( Zhao, Ren et al, 2019; Jiang et al, 2021a), resulting in uncertain usefulness of these degraders.…”

Section: Introductionmentioning

confidence: 99%

“…Currently, based on different ubiquitin E3 ligases, including VHL, CRBN and IAP, PROTAC-based degraders at nM level have shown significant degradation of BCR-ABL in CML cell lines, cell lines carrying mutations in BCR-ABL as well as patientderived primary cells containing multiple BCR-ABL mutations ( Demizu et al, 2016;Lai et al, 2016;Shimokawa et al, 2017;Zhao et al, 2019;Burslem et al, 2019;Liu et al, 2022) . Unfortunately, the excellent cellular activity by the PROTAC-based degraders .…”

Section: Introductionmentioning

confidence: 99%

RAPSYN-Mediated Neddylation of BCR-ABL Alternatively Determines the Fate of Philadelphia Chromosome-positive Leukemia

Zhao

Dai

et al. 2023

Preprint

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Philadelphia chromosome-positive (Ph+) leukemia is a fatal hematological malignancy. Although standard treatments with tyrosine kinase inhibitors (TKI) have achieved remarkable success in prolonging patient survival, intolerance, relapse and TKI resistance remain serious issues for patients with Ph+ leukemia. Here, we report a new leukemogenic process in which RAPSYN and BCR-ABL co-occur in Ph+ leukemia, and RAPSYN mediates the neddylation of BCR-ABL. Consequently, neddylated BCR-ABL enhances the stability by competing its c-CBL-mediated degradation. Furthermore, SRC phosphorylates RAPSYN to activate its NEDD8 E3 ligase activity, promoting BCR-ABL stabilization and disease progression. Moreover, in contrast to in vivo ineffectiveness of PROTAC-based degraders, depletion of RAPSYN expression or its ligase activity decreased BCR-ABL stability and, in turn, inhibited tumor formation and growth. Collectively, these findings represent an alternative to tyrosine kinase activity for the oncoprotein and leukemogenic cells and generate a rationale of targeting RAPSYN-mediated BCR-ABL neddylation for the treatment of Ph+ leukemia.

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“…Fluoroalkyl ethers are valuable structural motifs in the development of new pharmaceuticals, agrochemicals, and materials because the incorporation of fluoroalkoxy groups into organic compounds often alters their physical, chemical, and pharmacokinetic properties . Among these fluoroalkyl ethers, recently chloro- and bromodifluoromethyl aryl ethers (ArOCF 2 X, X: Cl, Br) are increasingly found as important moieties in biologically active compounds (Figure ) , because of the strength of their halogen bond interactions and their unconventional interaction geometries . For example, asciminib was approved by the FDA in 2021 as a BCR-ABL1 allosteric inhibitor .…”

mentioning

confidence: 99%

Copper-Mediated Oxidative Chloro- and Bromodifluoromethylation of Phenols

Yuan,

Tong,

et al. 2023

J. Am. Chem. Soc.

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The first oxidative chloro- and bromodifluoromethylation of phenols with (CH3)3SiCF2X and CuX (X = Cl or Br) in the presence of Selectfluor under mild reaction conditions was developed. This protocol provided a practical and efficient method for the synthesis of a diverse range of biologically valuable and synthetically challenging chloro- and bromodifluoromethyl aryl ethers. Preliminary mechanistic studies suggest that this reaction proceeded through a difluorocarbene-involved oxidative coupling process.

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Discovery and characterization of novel potent BCR-ABL degraders by conjugating allosteric inhibitor

Cited by 18 publications

References 61 publications

PROTACs: A novel strategy for cancer drug discovery and development

PROTACs: A novel strategy for cancer drug discovery and development

RAPSYN-Mediated Neddylation of BCR-ABL Alternatively Determines the Fate of Philadelphia Chromosome-positive Leukemia

Copper-Mediated Oxidative Chloro- and Bromodifluoromethylation of Phenols

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