Targeting Protein Kinases Degradation by PROTACs

Yu, Fei; Cai, Ming; Shao, Liang; Zhang, Jihong

doi:10.3389/fchem.2021.679120

Cited by 32 publications

(18 citation statements)

References 135 publications

(151 reference statements)

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“…Additionally, low doses of PROTACs can be highly effective at inducing degradation, which can reduce off-target toxicity associated with high-dosing of traditional inhibitors ( 3 ). PROTACs have been developed for a variety of cancer targets including oncogenic kinases ( 5 ), epigenetic targets ( 6 ) and recently KRAS G12C proteins ( 7 ). PROTACs targeting the androgen receptor or estrogen receptor are avidly being evaluated in clinical trials for prostate (NCT03888612) or breast cancers (NCT04072952) respectively.…”

Section: Introductionmentioning

confidence: 99%

MDR1 Drug Efflux Pump Promotes Intrinsic and Acquired Resistance to PROTACs in Cancer Cells

Kurimchak

Herrera-Montávez

Montserrat‐Sangrà

et al. 2021

Preprint

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PROTACs (Proteolysis-Targeting Chimeras) represent a promising new class of drugs that selectively degrade proteins of interest from cells. PROTACs targeting oncogenes are avidly being explored for cancer therapies, with several currently in clinical trials. Drug resistance represents a significant challenge in cancer therapies, and the mechanism by which cancer cells acquire resistance to PROTACs remains poorly understood. Using proteomics, we discovered acquired and intrinsic resistance to PROTACs in cancer cells can be mediated by upregulation of the drug efflux pump MDR1. PROTAC-resistant cells could be re-sensitized to PROTACs through co-administering MDR1 inhibitors. Notably, co-treatment of MDR1-overexpressing colorectal cancer cells with MEK1/2 or KRASG12C degraders and the dual ErbB receptor/MDR1 inhibitor lapatinib exhibited potent drug synergy due to simultaneous blockade of MDR1 and ErbB receptor activity. Together, our findings suggest that concurrent blockade of MDR1 will likely be required in combination with PROTACs to achieve durable protein degradation and therapeutic response in cancer.

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Section: Introductionmentioning

confidence: 99%

MDR1 Drug Efflux Pump Promotes Intrinsic and Acquired Resistance to PROTACs in Cancer Cells

Kurimchak

Herrera-Montávez

Montserrat‐Sangrà

et al. 2021

Preprint

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“…A potential answer to these problems could lie in the design and synthesis of LIMK specific PROTACs (Proteolysis-targeting chimeras). Although this strategy has been widely applied to different "undruggable" protein targets [68], relatively few papers have explicitly dealt with kinase degradation [69]. In the case of LIMK inhibition, a clear advantage is that instead of only targeting the active site to decrease or totally inhibit enzyme activity, a LIMK specific PROTAC would lead to the ubiquitination and degradation of the protein in the cell.…”

Section: Discussionmentioning

confidence: 99%

LIM Kinases, Promising but Reluctant Therapeutic Targets: Chemistry and Preclinical Validation In Vivo

Berabez

Routier

Bénédetti

et al. 2022

Cells

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LIM Kinases are important actors in the regulation of cytoskeleton dynamics by controlling microtubule and actin filament turnover. The signaling pathways involving LIM kinases for actin filament remodeling are well established. They are downstream effectors of small G proteins of the Rho-GTPases family and have become promising targets for the treatment of several major diseases because of their position at the lower end of these signaling cascades. Cofilin, which depolymerizes actin filaments, is the best-known substrate of these enzymes. The phosphorylation of cofilin to its inactive form by LIM kinases avoids actin filament depolymerization. The balance between phosphorylated and non-phosphorylated cofilin is thought to play an important role in tumor cell invasion and metastasis. Since 2006, many small molecules have been developed for LIMK inhibition, and in this review article, we will discuss the structure–activity relationships of the few inhibitor families that have been tested in vivo on different pathological models.

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“…The PROTAC molecule is then recycled for the next round of POI targeting. Thus, PROTACs act as small-molecule drugs that target POIs through an "event-driven" mode rather than an "occupation-driven" mode [81,82]. The advantages of PROTAC molecules include their ability to overcome drug resistance and target undruggable targets with low toxicity, and high efficiency and selectivity [83,84].…”

Section: Protacs and Mdm2-associated Degradersmentioning

confidence: 99%

PROTAC degraders with ligands recruiting MDM2 E3 ubiquitin ligase: an updated perspective

Han

Wei

Sun

2022

Acta Materia Medica

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Mouse double minute 2 (MDM2) is an oncogenic E3 ligase that effectively degrades the tumor suppressor p53. In the past two decades, many MDM2 inhibitors that disrupt MDM2-p53 binding have been discovered and developed. Given that MDM2 and p53 form an auto-regulatory loop, in which p53 undergoes targeted degradation as a substrate of MDM2, and p53 targets MDM2 for transcriptional upregulation, these MDM2 inhibitors have limited efficacy. After rapid in vivo clearance of the MDM2 inhibitors, p53 is degraded by accumulated MDM2. Fortunately, proteolysis targeting chimeras (PROTACs), a novel therapeutic strategy, overcome the limitations of MDM2 inhibitors. Several MDM2 inhibitors developed in the past two decades have been used in PROTAC technology in two applications: 1) binding and targeting endogenous MDM2 for PROTAC-based degradation and 2) binding endogenous MDM2 as a PROTAC E3 ligand for PROTAC-based degradation of other oncogenic proteins. In this review, we summarize current progress in the discovery and development of MDM2-based PROTAC drugs, and discuss future perspectives and challenges in their application as effective treatments for human cancer.

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Targeting Protein Kinases Degradation by PROTACs

Cited by 32 publications

References 135 publications

MDR1 Drug Efflux Pump Promotes Intrinsic and Acquired Resistance to PROTACs in Cancer Cells

MDR1 Drug Efflux Pump Promotes Intrinsic and Acquired Resistance to PROTACs in Cancer Cells

LIM Kinases, Promising but Reluctant Therapeutic Targets: Chemistry and Preclinical Validation In Vivo

PROTAC degraders with ligands recruiting MDM2 E3 ubiquitin ligase: an updated perspective

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