Single amino acid–based PROTACs trigger degradation of the oncogenic kinase BCR–ABL in chronic myeloid leukemia (CML)

Zhang, Jianchao; Ma, Caibing; Yu, Yang; Liu, Chaowei; Fang, Lijing; Rao, Hai

doi:10.1016/j.jbc.2023.104994

Cited by 5 publications

(7 citation statements)

References 48 publications

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“… 91 Among all, PROTAC arginine‐PEG1‐DAS (18) (DC 50 = 0.85 nM, D max = 98.8%) stands out, demonstrating good antileukemic activity both in vitro and in K562 xenograft mouse model in vivo. 91 …”

Section: Protacs Against Leukemia‐associated Targetsmentioning

confidence: 97%

“…In 2023, Rao et al. 91 expanded the toolbox of the E3 ligases and ligands effective for PROTACs, by designing a new typology of PROTACs, called single amino acid‐based PROTACs, targeting BCR‐ABL. These degraders present as ELM a single destabilizing amino acid that is recognized by a UBR E3 ligase, promoting target degradation via the N‐end rule pathway.…”

Section: Protacs Against Leukemia‐associated Targetsmentioning

confidence: 99%

“… 91 Therefore, PROTACs were synthesized with DAS as the TLM, linked by a PEG‐based linker, to a destabilizing amino acid (arginine, leucine, lysine, or phenylalanine). 91 When tested on CML cells, these PROTACs degraded BCR‐ABL and exhibited an antiproliferative effect with nanomolar potency. 91 It is worth noting that the results obtained with this type of PROTAC presented IC 50 and DC 50 values lower than most previous PROTACs, demonstrating that the use of N‐end rule‐based PROTACs allows to obtain degraders with lower molecular weight, potent and higher duration of action.…”

Section: Protacs Against Leukemia‐associated Targetsmentioning

confidence: 99%

“… 91 When tested on CML cells, these PROTACs degraded BCR‐ABL and exhibited an antiproliferative effect with nanomolar potency. 91 It is worth noting that the results obtained with this type of PROTAC presented IC 50 and DC 50 values lower than most previous PROTACs, demonstrating that the use of N‐end rule‐based PROTACs allows to obtain degraders with lower molecular weight, potent and higher duration of action. 91 Among all, PROTAC arginine‐PEG1‐DAS (18) (DC 50 = 0.85 nM, D max = 98.8%) stands out, demonstrating good antileukemic activity both in vitro and in K562 xenograft mouse model in vivo.…”

Section: Protacs Against Leukemia‐associated Targetsmentioning

confidence: 99%

“…In 2023, Rao et al 91 . expanded the toolbox of the E3 ligases and ligands effective for PROTACs, by designing a new typology of PROTACs, called single amino acid‐based PROTACs, targeting BCR‐ABL.…”

Section: Protacs Against Leukemia‐associated Targetsmentioning

confidence: 99%

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PROteolysis‐Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives

Vicente,

Salvador

2024

MedComm

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Leukemia is a heterogeneous group of life‐threatening malignant disorders of the hematopoietic system. Immunotherapy, radiotherapy, stem cell transplantation, targeted therapy, and chemotherapy are among the approved leukemia treatments. Unfortunately, therapeutic resistance, side effects, relapses, and long‐term sequelae occur in a significant proportion of patients and severely compromise the treatment efficacy. The development of novel approaches to improve outcomes is therefore an unmet need. Recently, novel leukemia drug discovery strategies, including targeted protein degradation, have shown potential to advance the field of personalized medicine for leukemia patients. Specifically, PROteolysis‐TArgeting Chimeras (PROTACs) are revolutionary compounds that allow the selective degradation of a protein by the ubiquitin–proteasome system. Developed against a wide range of cancer targets, they show promising potential in overcoming many of the drawbacks associated with conventional therapies. Following the exponential growth of antileukemic PROTACs, this article reviews PROTAC‐mediated degradation of leukemia‐associated targets. Chemical structures, in vitro and in vivo activities, pharmacokinetics, pharmacodynamics, and clinical trials of PROTACs are critically discussed. Furthermore, advantages, challenges, and future perspectives of PROTACs in leukemia are covered, in order to understand the potential that these novel compounds may have as future drugs for leukemia treatment.

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Section: Protacs Against Leukemia‐associated Targetsmentioning

confidence: 97%

Section: Protacs Against Leukemia‐associated Targetsmentioning

confidence: 99%