Targeted degradation of anaplastic lymphoma kinase by gold nanoparticle-based multi-headed proteolysis targeting chimeras

Wang, Ying‐Ming; Han, Lu; Liu, Fulei; Yang, Fubai; Jiang, Xueyang; Sun, Haopeng; Feng, Feng; Xue, Jingwei; Liu, Wenyuan

doi:10.1016/j.colsurfb.2020.110795

Cited by 34 publications

(37 citation statements)

References 50 publications

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“…As far as we know, nanotechnology has not been explored for PROTAC delivery. Only the recent work from Wang et al provides evidence for the development of a new concept for PROTAC design [ 25 ]. They prepared a nanoplatform for ALK target degradation.…”

Section: Discussionmentioning

confidence: 99%

“…Nanomedicine may have the potential to improve novel therapeutics for the treatment of solid tumors by optimizing the release of PROTACs through the use of vectorized nanocarriers. Very recently, Wang et al designed a novel nanoparticle-based PROTAC platform for the ALK target degradation as a potential therapeutic strategy to treat EML4-ALK-positive diseases [ 25 ]. This article was the proof of concept for the incorporation of PROTACs into nanoparticles.…”

Section: Introductionmentioning

confidence: 99%

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Controlled Delivery of BET-PROTACs: In Vitro Evaluation of MZ1-Loaded Polymeric Antibody Conjugated Nanoparticles in Breast Cancer

et al. 2020

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Bromo and extraterminal domain (BET) inhibitors-PROteolysis TArgeting Chimera (BETi-PROTAC) is a new family of compounds that induce proteasomal degradation through the ubiquitination of the tagged to BET inhibitors Bromodomain proteins, BRD2 and BRD. The encapsulation and controlled release of BET-PROTACs through their vectorization with antibodies, like trastuzumab, could facilitate their pharmacokinetic and efficacy profile. Antibody conjugated nanoparticles (ACNPs) using PROTACs have not been designed and evaluated. In this pioneer approach, the commercial MZ1 PROTAC was encapsulated into the FDA-approved polymeric nanoparticles. The nanoparticles were conjugated with trastuzumab to guide the delivery of MZ1 to breast tumoral cells that overexpress HER2. These ACNPs were characterized by means of size, polydispersity index, and Z-potential. Morphology of the nanoparticles, along with stability and release studies, completed the characterization. MZ1-loaded ACNPs showed a significant cytotoxic effect maintaining its mechanism of action and improving its therapeutic properties.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Controlled Delivery of BET-PROTACs: In Vitro Evaluation of MZ1-Loaded Polymeric Antibody Conjugated Nanoparticles in Breast Cancer

et al. 2020

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“…[ 28 ] Recently, three different RTKs were targeted using the PROTAC strategy: the FMS‐like tyrosine kinase 3 (FLT3), [ 29 ] the tropomyosin receptor kinase C (TrkC), [ 30 ] and the anaplastic lymphoma kinase (ALK). [ 31,32 ]…”

Section: Receptor Tyrosine Kinases (Rtks) Degradersmentioning

confidence: 99%

“…In fact, the authors described a multiheaded PROTAC by connecting several POI and E3 UL ligands on gold nanoparticles (GNPs). [ 32 ] There are multiple interests using this methodology, even if the efficacy of this first generation of GNP needs to be improved. [ 57 ] Indeed, GNP could be easily functionalized due to the strong binding affinity of gold for thiol functions.…”

Section: Receptor Tyrosine Kinases (Rtks) Degradersmentioning

confidence: 99%

“…Despite these mixed results, multivalency properties brought by GNP could offer a promising strategy to increase the probability of putting the POI and the E3 UL into close proximity, which consequently promotes the formation of the ternary complex. [ 32 ] Further investigations, in particular in vivo evaluations, are necessary to evaluate the interest of such approach.…”

Section: Receptor Tyrosine Kinases (Rtks) Degradersmentioning

confidence: 99%

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PROteolysis TArgetting Chimeras (PROTACs) Strategy Applied to Kinases: Recent Advances

Feral

Laconde

Amblard

et al. 2020

Advanced Therapeutics

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Since the development of the first protein kinase inhibitor in the early 1980s, followed by the FDA approval of imatinib in 2001, kinases are one of the most intensively pursued targets in current medicinal chemistry research. These proteins are overrepresented in various diseases such as cancer, inflammation or autoimmune pathologies and play important roles in their physiopathogenic processes. Despite the development and approval of numerous potent kinase inhibitors, drug resistance and off‐target side effects are commonly encountered with kinase inhibitors. Thus, development of novel strategies to overcome these problems is necessary. Since 2013, many research groups have proposed the conversion of potent kinase inhibitors into PROteolysis TArgeting Chimera (PROTAC) compounds and shared relevant and encouraging results using this new technology, which degrades proteins by employing the cellular machinery. Generally, this strategy brings enhancements in biological effects compared to the use of only the parent inhibitor. In this review article, recent findings related to the PROTAC technology applied to kinases are discussed, with a special focus on publications since 2018.

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Establishment and validation of a sensitive LC–MS/MS method for the quantification of KRAS^G12C protein PROTAC molecule LC‐2 in rat plasma and its application to in vivo pharmacokinetic studies of LC‐2 PEGylated liposomes

Wang

Wang²,

Wang

et al. 2023

Biomedical Chromatography

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LC‐2, is a molecule of proteolysis targeting chimeras (PROTACs), with a large molecular weight, poor water solubility and low system bioavailability, which was designed to degrade KRASG12C protein. In this study, LC‐2 PEGylated liposomes were developed and characterized. Moreover, a rapid and sensitive liquid chromatography–tandem mass spectrometry (LC–MS/MS) method in rat plasma was established and effectively utilized for an in vivo pharmacokinetic investigation. LC‐2 PEGylated liposomes with better properties were prepared by an improved ethanol injection method. The chromatographic separation was achieved on an Agilent Eclipse XDB‐CN column (100 × 2.1 mm, 3.5 μm) with acetonitrile–ammonium deionized water (5 mm; 80:20, v/v) at a flow rate of 0.5 ml/min. The mass spectra of LC‐2 and the IS (gefitinib) were obtained at m/z 1132.5 → 626.4 and 447.1 → 128.2, respectively. The pharmacokinetic study was carried out by analyzing plasma concentrations of LC‐2 solution or produced LC‐2 PEGylated liposomes in rats using the developed and validated method. The pharmacokinetic results indicate that PEGylated liposome‐encapsulation protected LC‐2 from the influence of endogenous protein binding, improved insolubility, prolonged half‐life and increased system bioavailability. This study provides a feasible solution for future preclinical and clinical studies of LC‐2 and/or other PROTACs.

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Targeted degradation of anaplastic lymphoma kinase by gold nanoparticle-based multi-headed proteolysis targeting chimeras

Cited by 34 publications

References 50 publications

Controlled Delivery of BET-PROTACs: In Vitro Evaluation of MZ1-Loaded Polymeric Antibody Conjugated Nanoparticles in Breast Cancer

Controlled Delivery of BET-PROTACs: In Vitro Evaluation of MZ1-Loaded Polymeric Antibody Conjugated Nanoparticles in Breast Cancer

PROteolysis TArgetting Chimeras (PROTACs) Strategy Applied to Kinases: Recent Advances

Establishment and validation of a sensitive LC–MS/MS method for the quantification of KRAS^G12C protein PROTAC molecule LC‐2 in rat plasma and its application to in vivo pharmacokinetic studies of LC‐2 PEGylated liposomes

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Targeted degradation of anaplastic lymphoma kinase by gold nanoparticle-based multi-headed proteolysis targeting chimeras

Cited by 34 publications

References 50 publications

Controlled Delivery of BET-PROTACs: In Vitro Evaluation of MZ1-Loaded Polymeric Antibody Conjugated Nanoparticles in Breast Cancer

Controlled Delivery of BET-PROTACs: In Vitro Evaluation of MZ1-Loaded Polymeric Antibody Conjugated Nanoparticles in Breast Cancer

PROteolysis TArgetting Chimeras (PROTACs) Strategy Applied to Kinases: Recent Advances

Establishment and validation of a sensitive LC–MS/MS method for the quantification of KRASG12C protein PROTAC molecule LC‐2 in rat plasma and its application to in vivo pharmacokinetic studies of LC‐2 PEGylated liposomes

Contact Info

Product

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Establishment and validation of a sensitive LC–MS/MS method for the quantification of KRAS^G12C protein PROTAC molecule LC‐2 in rat plasma and its application to in vivo pharmacokinetic studies of LC‐2 PEGylated liposomes