Identification of PKMYT1 inhibitors by screening the GSK published protein kinase inhibitor set I and II

Chen

Liu

et al. 2020

OTT

Background: Abnormal expression of protein kinase membrane associated tyrosine/threonine 1 (PKMYT1) is closely associated with multiple types of cancers. In the present study, we examined the roles of PKMYT1 in gastric cancer (GC) progression. Methods: We examined the expression status of PKMYT1 in GC tissues and cell lines. Meanwhile, short hairpin RNA (shRNA) was used to inhibit the endogenous expression of PKMYT1 in GC cells. Then we analyzed the effect of PKMYT1 on the malignant biological behavior of GC cells by in vitro and in vivo experiments. Results: The findings showed high PKMYT1 expressions in GC tissues as well as a positive correlation between PKMYT1 expression and prognosis of patients with GC. Additional findings also revealed that PKMYT1 silencing significantly enhanced apoptosis and inhibited GC cell proliferation. In vivo, the silence of PKMYT1 inhibits tumor growth. Further analysis showed that the increase in PKMYT1 expressions led to malignant biological behavior through activation of the MAPK signaling pathway. Conclusion: Our data suggested that PKMYT1 promotes cell proliferation and apoptosis resistance in GC cells by activating the MAPK signaling pathway, making it a potential therapeutic target for GC.

Section: Discussionmentioning

confidence: 99%

PKMYT1 Promotes Gastric Cancer Cell Proliferation and Apoptosis Resistance

Chen

Liu

et al. 2020

OTT

“…The WEE1 inhibitor MK1775 is currently being in clinical trials to treat various solid tumors combined with chemotherapy 45,46. Several PKMYT1 inhibitors have been already developed, including the well-known tyrosine kinase inhibitors dasatinib and bosutinib, the pyridopyrimidine derivatives PD-0166285, PD-173952, PD-173955, and PD-180970 also have been identified by applying different approaches,47–49 and more novel molecular inhibitors are underway 50,51…”

Section: Discussionmentioning

confidence: 99%

Overexpressed PKMYT1 promotes tumor progression and associates with poor survival in esophageal squamous cell carcinoma

Zhao

et al. 2019

CMAR

BackgroundEsophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors worldwide and the 5-year overall survival rate remains poor. Protein kinase, membrane associated tyrosine/threonine (PKMYT1) is overexpressed in several cancers and participate in tumor progression. However, the mechanism of PKMYT1 in ESCC is unclear.PurposeThe objective of our study was to demonstrate the the expression and role of PKMYT1 in ESCC.Patients and methods We detected the expression of PKMYT1 in ESCC patients and analysed the correlation with overall survival time and disease-free survival time. Then we detected PKMYT1 expression in ESCC cell lines and immortalized human esophageal epithelial cell line. Down-regulated PKMYT1 was carried out in KYSE70 and KYSE450 cells to invetigate the mechanism of PKMYT1 in ESCC cells.ResultsPKMYT1 was up-regulated in tumor tissues and ESCC cell lines, and higher expression of PKMYT1 correlated with poorer overall survival in ESCC patients. Besides, in ESCC cell lines KYSE70 and KYSE450, knocking down PKMYT1 allowed more cells to skip G2/M checkpoint to complete mitosis, which promoted cell apoptosis, inhibited cell proliferation, and prevented the EMT phenotype in vitro. Meantime, we also observed that down-regulated PKMYT1 in ESCC cells suppressed AKT/mTOR signaling pathway. These results demonstrated PKMYT1 may act as an oncogene in ESCC.ConclusionPKMYT1 plays an crutial role in ESCC progression, downregulated PKMYT1 might inhibit the development of ESCC by AKT/mTOR signaling pathway, and might be a novel target in the treatment of ESCC.

Briefings in Bioinformatics

“…Among these, the membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase (PKMYT1), a compelling target for treating specific types of DNA damage response-related cancers due to its established synthetic lethal connection with CCNE1 amplification [ 35 ], is of particular interest and has been selected in the early stages of DKKB project. PKMYT1 is a highly selective kinase that is difficult to inhibit compared to other kinases [ 36 , 37 ]. According to a comprehensive analysis of kinase inhibitor selectivity by Davis et al.…”

Section: Resultsmentioning

confidence: 99%

KinomeMETA: meta-learning enhanced kinome-wide polypharmacology profiling

Ren,

Qu,

Sun

et al. 2023

Kinase inhibitors are crucial in cancer treatment, but drug resistance and side effects hinder the development of effective drugs. To address these challenges, it is essential to analyze the polypharmacology of kinase inhibitor and identify compound with high selectivity profile. This study presents KinomeMETA, a framework for profiling the activity of small molecule kinase inhibitors across a panel of 661 kinases. By training a meta-learner based on a graph neural network and fine-tuning it to create kinase-specific learners, KinomeMETA outperforms benchmark multi-task models and other kinase profiling models. It provides higher accuracy for understudied kinases with limited known data and broader coverage of kinase types, including important mutant kinases. Case studies on the discovery of new scaffold inhibitors for membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase and selective inhibitors for fibroblast growth factor receptors demonstrate the role of KinomeMETA in virtual screening and kinome-wide activity profiling. Overall, KinomeMETA has the potential to accelerate kinase drug discovery by more effectively exploring the kinase polypharmacology landscape.