Design, Synthesis, and Biological Evaluation of MEK PROTACs

Vollmer, Stefan; Cunoosamy, Danen; Lv, Hang; Feng, Huanxi; Li, Xia; Nan, Ziyang; Yang, Wenzhen; Perry, Matthew W. D.

doi:10.1021/acs.jmedchem.9b00810

Cited by 40 publications

(31 citation statements)

References 20 publications

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“…What's more, taking advantage of haloPROTACs, a ligand-inducible tractable affinity-directed protein missile system (L-AdPROM), in which aHRAS conjugated to the Halo-tag and tagged with a FLAG reporter, successfully degraded RAS and reduce the RAS-driven signaling in A549 cells [199]. In addition, PROTACs regarding some targets in RAS signaling pathway, such as MEK, PDEδ, TBK1 and SHP2, also successfully degraded the corresponding targets and suppressed the RAS signaling in vitro or in vivo [200][201][202][203].…”

Section: Other Strategies Of Targeting Mutant Rasmentioning

confidence: 99%

Emerging strategies to target RAS signaling in human cancer therapy

et al. 2021

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RAS mutations (HRAS, NRAS, and KRAS) are among the most common oncogenes, and around 19% of patients with cancer harbor RAS mutations. Cells harboring RAS mutations tend to undergo malignant transformation and exhibit malignant phenotypes. The mutational status of RAS correlates with the clinicopathological features of patients, such as mucinous type and poor differentiation, as well as response to anti-EGFR therapies in certain types of human cancers. Although RAS protein had been considered as a potential target for tumors with RAS mutations, it was once referred to as a undruggable target due to the consecutive failure in the discovery of RAS protein inhibitors. However, recent studies on the structure, signaling, and function of RAS have shed light on the development of RAS-targeting drugs, especially with the approval of Lumakras (sotorasib, AMG510) in treatment of KRASG12C-mutant NSCLC patients. Therefore, here we fully review RAS mutations in human cancer and especially focus on emerging strategies that have been recently developed for RAS-targeting therapy.

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Section: Other Strategies Of Targeting Mutant Rasmentioning

confidence: 99%

Emerging strategies to target RAS signaling in human cancer therapy

et al. 2021

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“…Vollmer et al designed PROTAC 4 ( 45 , Figure 8 ) according to PEG linker and allosteric MEK inhibitors. Although PROTAC 4 is less effective in inhibiting ERK1/2 phosphorylation, it is more potent in inhibiting A375 cell proliferation ( Vollmer et al, 2020 ).…”

Section: Recent Progress Of Protacs Targeting Protein Kinasementioning

confidence: 99%

Targeting Protein Kinases Degradation by PROTACs

Cai

Shao

et al. 2021

Front. Chem.

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Kinase dysregulation is greatly associated with cell proliferation, migration and survival, indicating the importance of kinases as therapeutic targets for anticancer drug development. However, traditional kinase inhibitors binding to catalytic or allosteric sites are associated with significant challenges. The emergence of resistance and targeting difficult-to-degrade and multi-domain proteins are significant limiting factors affecting the efficacy of targeted anticancer drugs. The next-generation treatment approaches seem to have overcome these concerns, and the use of proteolysis targeting chimera (PROTAC) technology is one such method. PROTACs bind to proteins of interest and recruit E3 ligase for degrading the whole target protein via the ubiquitin-proteasome pathway. This review provides a detailed summary of the most recent signs of progress in PROTACs targeting different kinases, primarily focusing on new chemical entities in medicinal chemistry.

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“…Proteolysis targeting chimerics (PROTACs), also known as bivalent chemical protein degraders, are heterobifunctional molecules that degrade specific endogenous proteins through the E3 ubiquitin ligase pathway (Potjewyd et al, 2020). It structurally connects the protein of interest (POI)-binding ligand and the E3 ubiquitin ligase (E3) ligand through an appropriate linker (Buckley et al, 2015;Zhang et al, 2019;Kregel et al, 2020;Vollmer et al, 2020). The potential advantages of PROTAC technology may compensate for the shortcomings of traditional drug therapy, which promotes its rapid development (Toure and Crews, 2016;Sun and Rao, 2020).…”

Section: Introductionmentioning

confidence: 99%

PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy

et al. 2021

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Proteolysis targeting chimeric (PROTAC) technology is an effective endogenous protein degradation tool developed in recent years that can ubiquitinate the target proteins through the ubiquitin-proteasome system (UPS) to achieve an effect on tumor growth. A number of literature studies on PROTAC technology have proved an insight into the feasibility of PROTAC technology to degrade target proteins. Additionally, the first oral PROTACs (ARV-110 and ARV-471) have shown encouraging results in clinical trials for prostate and breast cancer treatment, which inspires a greater enthusiasm for PROTAC research. Here we focus on the structures and mechanisms of PROTACs and describe several classes of effective PROTAC degraders based on E3 ligases.

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Design, Synthesis, and Biological Evaluation of MEK PROTACs

Cited by 40 publications

References 20 publications

Emerging strategies to target RAS signaling in human cancer therapy

Emerging strategies to target RAS signaling in human cancer therapy

Targeting Protein Kinases Degradation by PROTACs

PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy

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