Discovery of a PROTAC targeting ALK with in vivo activity

Yan, Guohua; Zhong, Xinxin; Yang, Lin; Pu, Chun; Shan, Huifang; Lan, Suke; Zhou, Meng; Hou, Xueyan; Yang, Jie; Li, Rui

doi:10.1016/j.ejmech.2020.113150

Cited by 37 publications

(33 citation statements)

References 37 publications

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“…Subsequently, Wei’s group introduced a light-inducible switch on 8a , named opto-PROTAC 8b (opto-dALK), which enables the degradation of ALK in a spatiotemporal manner . Hwang and Li’s groups also developed ALK degraders 9 (TD-004) and 10 (B3) by linking ceritinib ( 2 ) to Von Hippel–Lindau (VHL) and CRBN E3 ligases, respectively. , Both of them showed acceptable efficacy in reducing tumor growth in the H3122 xenograft model. Very recently, Jiang’s group reported brigatinib ( 4 )-based degrader 11 (SIAIS117), which can degrade the G1202R mutant ALK protein in vitro .…”

Section: Introductionmentioning

confidence: 99%

Development of Alectinib-Based PROTACs as Novel Potent Degraders of Anaplastic Lymphoma Kinase (ALK)

et al. 2021

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A series of novel anaplastic lymphoma kinase (ALK) degraders were designed and synthesized based on proteolysis-targeting chimera (PROTAC) technology by linking two alectinib analogs (36 and 37) with pomalidomide through linkers of different lengths and types. The most promising degrader 17 possessed a high ALK-binding affinity and potent antiproliferative activity in the ALK-dependent cell lines and did not exhibit obvious cytotoxicity in ALK fusion-negative cells. More importantly, the efficacy of compound 17 in a Karpas 299 xenograft mouse model was further evaluated based on its ALK-sustained degradation ability in vivo. The reduction in tumor weight in the compound 17-treated group (10 mg/kg/day, I.V.) reached 75.82%, while alectinib reduced tumor weight by 63.82% at a dose of 20 mg/kg/day (P.O.). Taken together, our findings suggest that alectinib-based PROTACs associated with the degradation of ALK may have promising beneficial effects for treating ALK-driven malignancies.

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Section: Introductionmentioning

confidence: 99%

Development of Alectinib-Based PROTACs as Novel Potent Degraders of Anaplastic Lymphoma Kinase (ALK)

et al. 2021

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“…In 2021, Li group also reported a new series of ALK degraders based on Ceritinib and pomalidomide. 126 The degrader 68 ( B3 , Fig. 19 ) showed potent selective inhibitory activity to ALK (IC 50 = 1.6 nM) and could decrease the level of ALK fusion protein in H3122 cells.…”

Section: Protacs Targeting Cancer-related Targetsmentioning

confidence: 99%

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

Cao

et al. 2022

Sig Transduct Target Ther

136

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PROteolysis TArgeting Chimeras (PROTACs) technology is a new protein-degradation strategy that has emerged in recent years. It uses bifunctional small molecules to induce the ubiquitination and degradation of target proteins through the ubiquitin–proteasome system. PROTACs can not only be used as potential clinical treatments for diseases such as cancer, immune disorders, viral infections, and neurodegenerative diseases, but also provide unique chemical knockdown tools for biological research in a catalytic, reversible, and rapid manner. In 2019, our group published a review article “PROTACs: great opportunities for academia and industry” in the journal, summarizing the representative compounds of PROTACs reported before the end of 2019. In the past 2 years, the entire field of protein degradation has experienced rapid development, including not only a large increase in the number of research papers on protein-degradation technology but also a rapid increase in the number of small-molecule degraders that have entered the clinical and will enter the clinical stage. In addition to PROTAC and molecular glue technology, other new degradation technologies are also developing rapidly. In this article, we mainly summarize and review the representative PROTACs of related targets published in 2020–2021 to present to researchers the exciting developments in the field of protein degradation. The problems that need to be solved in this field will also be briefly introduced.

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“…Except for these targets, the following proteins related to cancer cell proliferation could also be targeted by PROATCs: AR [ 7 , 106 , 108 – 111 , 155 , 156 ], ALK [ 22 , 52 , 113 , 116 , 157 ], BLK [ 118 ], BRD7/9 [ 82 , 83 , 120 , 158 ], CDK2/5 [ 84 ], CDK8 [ 112 ], CDK9 [ 38 , 114 , 115 , 117 , 159 ], Cdc20 [ 119 ], c-Met [ 79 ], CREPT [ 121 ], CYP1B1 [ 122 ], DHODH [ 123 ], ER [ 89 , 124 , 126 , 128 , 160 ], ERK1/2 [ 26 ], FLT-3 [ 132 , 161 ], HER2 [ 79 ], MEK1/2 [ 85 , 86 , 162 ], KRAS G12C [ 87 , 163 ], GSPT1 [ 125 ], PLK1 [ 127 ], SLC9A1 [ 129 ], TACC3 [ 130 ], TRIM24 [ 131 ], TRKA/C [ 133 , 164 ], Wee1 [ 88 ], α 1A -AR [ 134 ].…”

Section: Protacs In Targeted Cancer Therapymentioning

confidence: 99%

Proteolysis-targeting chimeras (PROTACs) in cancer therapy

Zheng

et al. 2022

Mol Cancer

150

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Proteolysis-targeting chimeras (PROTACs) are engineered techniques for targeted protein degradation. A bifunctional PROTAC molecule with two covalently-linked ligands recruits target protein and E3 ubiquitin ligase together to trigger proteasomal degradation of target protein by the ubiquitin-proteasome system. PROTAC has emerged as a promising approach for targeted therapy in various diseases, particularly in cancers. In this review, we introduce the principle and development of PROTAC technology, as well as the advantages of PROTACs over traditional anti-cancer therapies. Moreover, we summarize the application of PROTACs in targeting critical oncoproteins, provide the guidelines for the molecular design of PROTACs and discuss the challenges in the targeted degradation by PROTACs.

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Discovery of a PROTAC targeting ALK with in vivo activity

Cited by 37 publications

References 37 publications

Development of Alectinib-Based PROTACs as Novel Potent Degraders of Anaplastic Lymphoma Kinase (ALK)

Development of Alectinib-Based PROTACs as Novel Potent Degraders of Anaplastic Lymphoma Kinase (ALK)

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

Proteolysis-targeting chimeras (PROTACs) in cancer therapy

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