Research progress of MEK1/2 inhibitors and degraders in the treatment of cancer

Wang, Chao; Wang, Han; Zheng, Cangxin; Liu, Zhenming; Gao, X.; Xu, Fengrong; Niu, Yan; Zhang, Liangren; Xu, Ping

doi:10.1016/j.ejmech.2021.113386

Cited by 33 publications

(21 citation statements)

References 98 publications

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“…The MAP kinase cascade is the most important oncogenic driver of human cancers, and blocking this signaling module by targeted inhibitors is a promising antitumor strategy (16). Since MEK1/2 have very narrow substrate specificity, MEK1/2 inhibition specifically shuts off ERK1/2 signaling without affecting other signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Tegaserod maleate suppresses the growth of gastric cancer in vivo and in vitro by targeting MEK1/2

Liu

Jiang

Wang

et al. 2022

Preprint

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Gastric cancer (GC), ranking fifth in global incidence and fourth in mortality. The current treatments for GC include surgery, chemotherapy, and radiotherapy. Although management and treatment strategies for GC have been improved over the last decade, the overall five-year survival rate remains less than 30%. Therefore, there is an urgent need to find novel therapeutic or preventive strategies that can increase GC patient survival rates. In the current study, we found that tegaserod maleate, a FDA-approved drug, could inhibit the proliferation of gastric cancer cells. Tegaserod maleate binds to MEK1 /2 and inhibits MEK1 /2 kinase activity. Moreover, the construction of CRISPER/Cas9 cell line further verified that tegaserod maleate depended on MEK1 /2 to inhibit the progress of GC. Notably, we found that tegaserod maleate suppressed tumor growth in patient-derived gastric xenograft (PDX) mouse model. We also compared tegaserod maleate with trametinib, a clinical MEK1/2 inhibitor, and comfirmed that tegaserod maleate have the same effect in inhibiting tumor volume and tumor weight. Our findings suggest that tegaserod maleate can inhibit GC proliferation by targeting MEK1/2.

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Section: Discussionmentioning

confidence: 99%

Tegaserod maleate suppresses the growth of gastric cancer in vivo and in vitro by targeting MEK1/2

Liu

Jiang

Wang

et al. 2022

Preprint

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“…Mitogen-activated protein kinases 1 and 2 (MEK1/2) are one of the crucial enz of the ERK pathway. [51] The use of MEK inhibitors is limited due to the acquire sistance towards them in patients undergoing long-term treatment. However, since tations in MEK1/2 induce resistance to MEK inhibitors, the opportunity to overcom should be investigated via MEK1/2 degradation and PROTAC technology.…”

Section: Mek1/2 Degradermentioning

confidence: 99%

“…Mitogen-activated protein kinases 1 and 2 (MEK1/2) are one of the crucial enzymes of the ERK pathway [51]. The use of MEK inhibitors is limited due to the acquired resistance towards them in patients undergoing long-term treatment.…”

Section: Mek1/2 Degradermentioning

confidence: 99%

Small-Molecule Inhibitors and Degraders Targeting KRAS-Driven Cancers

Hyun

Shin

2021

IJMS

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Drug resistance continues to be a major problem associated with cancer treatment. One of the primary causes of anticancer drug resistance is the frequently mutated RAS gene. In particular, considerable efforts have been made to treat KRAS-induced cancers by directly and indirectly controlling the activity of KRAS. However, the RAS protein is still one of the most prominent targets for drugs in cancer treatment. Recently, novel targeted protein degradation (TPD) strategies, such as proteolysis-targeting chimeras, have been developed to render “undruggable” targets druggable and overcome drug resistance and mutation problems. In this study, we discuss small-molecule inhibitors, TPD-based small-molecule chemicals for targeting RAS pathway proteins, and their potential applications for treating KRAS-mutant cancers. Novel TPD strategies are expected to serve as promising therapeutic methods for treating tumor patients with KRAS mutations.

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“…The extracellular signal-regulated kinase pathway (also known as the Ras-Raf-MEK-ERK pathway) is an evolutionarily conserved signal-transduction cascade that regulates diverse cellular functions including cell proliferation, differentiation, migration and survival (Seger & Krebs, 1995;Kolch, 2000;McCubrey et al, 2007). The mitogen-activated protein kinase (MAPK) kinases (MEK1 and MEK2) are key components of the pathway that catalyse the phosphorylation of their only known physiological substrates, ERK1 and ERK2 (Wang et al, 2021). MEK1 and MEK2, the amino-acid sequences of which share over 80% identity (Zheng & Guan, 1993), are activated by Raf kinases through the dual phosphorylation of two neighboring serine residues in their activating segment (Ser218/Ser222 in human MEK1 and Ser222/Ser226 in human MEK2; Roskoski, 2012).…”

Section: Introductionmentioning

confidence: 99%

Structure of mitogen-activated protein kinase kinase 1 in the DFG-out conformation

et al. 2021

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Eukaryotic protein kinases contain an Asp-Phe-Gly (DFG) motif, the conformation of which is involved in controlling the catalytic activity, at the N-terminus of the activation segment. The motif can be switched between active-state (DFG-in) and inactive-state (DFG-out) conformations: however, the mechanism of conformational change is poorly understood, partly because there are few reports of the DFG-out conformation. Here, a novel crystal structure of nonphosphorylated human mitogen-activated protein kinase kinase 1 (MEK1; amino acids 38–381) complexed with ATP-γS is reported in which MEK1 adopts the DFG-out conformation. The crystal structure revealed that the structural elements (the αC helix and HRD motif) surrounding the active site are involved in the formation/stabilization of the DFG-out conformation. The ATP-γS molecule was bound to the canonical ATP-binding site in a different binding mode that has never been found in previously determined crystal structures of MEK1. This novel ATP-γS binding mode provides a starting point for the design of high-affinity inhibitors of nonphosphorylated inactive MEK1 that adopts the DFG-out conformation.

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Research progress of MEK1/2 inhibitors and degraders in the treatment of cancer

Cited by 33 publications

References 98 publications

Tegaserod maleate suppresses the growth of gastric cancer in vivo and in vitro by targeting MEK1/2

Tegaserod maleate suppresses the growth of gastric cancer in vivo and in vitro by targeting MEK1/2

Small-Molecule Inhibitors and Degraders Targeting KRAS-Driven Cancers

Structure of mitogen-activated protein kinase kinase 1 in the DFG-out conformation

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