Discovery of a small molecule targeting ULK1-modulated cell death of triple negative breast cancer in vitro and in vivo

Zhang, Lan; Fu, Leilei; Zhang, Shouyue; Zhang, Jin; Zhao, Yuqian; Zheng, Yaxin; He, Gu; Yang, Shengyong; Ouyang, Liang; Liu, Bo

doi:10.1039/c6sc05368h

Cited by 129 publications

(128 citation statements)

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“…Moreover, we noticed that all the other experimental mutations with a reported effect on ULK1 activity are predicted to have marginal effects on protein stability, with the exception of K46N, M92A and Y89A. These mutations result either in an inactivation of the kinase [120] or an impairment of phosphorylation of the ATG13 substrate [27]. Our calculations suggest that an additional detrimental effect can come from altering the native stability of the protein, an aspect which could deserve further investigation to verify the cellular levels and half-life of these variants to assess which one is the predominant effect.…”

Section: General Assessment and Classification Of Ulk1 Missense Mutatmentioning

confidence: 91%

“…The framework here applied could be extended more broadly to other targets to help in the classification of mutational effects in disease, to prioritize variants for experimental validation or select the appropriate biological readouts for experiments.suggested to play essential scaffolding roles for autophagosome formation and maturation [9]. ULK1 has been reported overexpressed or downregulated in different cancer types or subtypes [25][26][27][28]. Autophagy in general has a strong association with cancer and can act with a dual role in a context-dependent way, being both tumor suppressor or promoter [29,30].…”

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confidence: 99%

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A Pan-Cancer assessment of alterations of the kinase domain of ULK1, an upstream regulator of autophagy

Kumar

Papaleo

2019

Preprint

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Autophagy is a key clearance process for the cell to recycle damaged cellular components. Autophagy is also well known for its dual role in cancer, acting as both tumor suppressor or promoter in a context-dependent way. One important upstream regulator of autophagy is the kinase ULK1. Several structures of the kinase domain of ULK1 have been solved, but a comprehensive study, including molecular dynamics, is currently missing. Also, an exhaustive description of the landscape of ULK1 cancer-related alterations is presently lacking. We here exploited the large amount of data on more than 30 cancer types through The Cancer Genome Atlas and the Recount2 initiatives to identify and analyze the atlas of ULK1 alterations in terms of gene expression and mutations. Moreover, we predicted the effects of mutations on ULK1 function and structural stability using a computational workflow accounting for protein dynamics and different layers of changes that a mutation can induce in a protein.We discovered that ULK1, along with ULK2 are down-regulated in gynecological tumors, suggesting an impairment of the upstream regulation of autophagy. In other cancer types, ULK2 can compensate for ULK1 downregulation and, in the majority of the cases, no marked changes in expression level have been found for both genes. We identified 36 missense mutations of ULK1 especially in uterine, colon, stomach and lung cancer that were co-occurring with mutations in a large number of ULK1 interactors, suggesting a pronounced effect of the upstream steps of autophagy in these cancer types. Moreover, our study allowed to pinpoint that more than 50% of the mutations of ULK1 found in the cancer samples affect protein stability, which is likely to affect the cellular level and turnover of the protein. Among the damaging mutations for stability, A125T, F273V, L215P, F14L, and G12D are also predicted not to alter the functional state of the protein. Three mutations (S184F, D102N, and A28V) are predicted with the only impact on kinase activity, either modifying the functional dynamics of the protein or the capability to exert effects from distal site to the functional and catalytic regions. The framework here applied could be extended more broadly to other targets to help in the classification of mutational effects in disease, to prioritize variants for experimental validation or select the appropriate biological readouts for experiments.suggested to play essential scaffolding roles for autophagosome formation and maturation [9]. ULK1 has been reported overexpressed or downregulated in different cancer types or subtypes [25][26][27][28]. Autophagy in general has a strong association with cancer and can act with a dual role in a context-dependent way, being both tumor suppressor or promoter [29,30]. AMPK-ULK1 mediated autophagy also induces resistance against bromodomain and extraterminal domain inhibitors, which are novel epigenetic therapeutics for acute myeloid leukemia [31].So it can be a pivotal target to curb the chemotherapeutic resistance in cancers....

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Section: General Assessment and Classification Of Ulk1 Missense Mutatmentioning

confidence: 91%

mentioning

confidence: 99%

A Pan-Cancer assessment of alterations of the kinase domain of ULK1, an upstream regulator of autophagy

Kumar

Papaleo

2019

Preprint

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“…Autophagy, a term from Greek “auto” (self) and “phagy” (to eat), refers to an evolutionarily conserved cellular mechanism for the clearance of damaged or superfluous organelles, such as endoplasmic reticulum, golgi apparatus and mitochondria . Recent work suggests that autophagy is important in cell death decisions and can protect cells from apoptosis and caspase‐independent death .…”

Section: Introductionmentioning

confidence: 99%

“…clearance of damaged or superfluous organelles, such as endoplasmic reticulum, golgi apparatus and mitochondria. [8][9][10] Recent work suggests that autophagy is important in cell death decisions and can protect cells from apoptosis and caspase-independent death. 11 However, unusual levels of autophagy can also do the opposite-it can also kill cells.…”

Section: Introductionmentioning

confidence: 99%

Fluoxetine induces autophagic cell death via eEF2K‐AMPK‐mTOR‐ULK complex axis in triple negative breast cancer

et al. 2017

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“…Further optimization led to the synthesis of the most potent compound LYN‐1604 ( 32 ) which showed an EC 50 value of 19 nM. Interestingly, 32 exhibited good therapeutic potential in TNBC in vivo …”

Section: Autophagy Modulators In Oscc and Esccmentioning

confidence: 99%

Autophagy modulators for the treatment of oral and esophageal squamous cell carcinomas

Khan

Relitti

Brindisi

et al. 2019

Medicinal Research Reviews

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Oral squamous cell carcinomas (OSCC) and esophageal squamous cell carcinomas (ESCC) exhibit a survival rate of less than 60% and 40%, respectively. Late-stage diagnosis and lack of effective treatment strategies make both OSCC and ESCC a significant health burden. Autophagy, a lysosome-dependent catabolic process, involves the degradation of intracellular components to maintain cell homeostasis. Targeting autophagy has been highlighted as a feasible therapeutic strategy with clinical utility in cancer treatment, although its associated regulatory mechanisms remain elusive. The detection of relevant biomarkers in biological fluids has been anticipated to facilitate early diagnosis and/or prognosis for these tumors. In this context, recent studies have indicated the presence of specific proteins and small RNAs, detectable in circulating plasma and serum, as biomarkers. Interestingly, the interplay between biomarkers (eg, exosomal microRNAs) and autophagic processes could be exploited in the quest for targeted and more effective therapies for OSCC and ESCC. In this review, we give an overview of the available biomarkers and innovative targeted therapeutic strategies, including the application of autophagy modulators in OSCC and ESCC.Additionally, we provide a viewpoint on the state of the art Tuhina Khan and Nicola Relitti contributed equally to this work. and on future therapeutic perspectives combining the early detection of relevant biomarkers with drug discovery for the treatment of OSCC and ESCC. K E Y W O R D S autophagy, autophagy modulators, biomarkers, esophageal squamous cell carcinoma, exosomes, oral squamous cell carcinoma, targeted therapy 1 | INTRODUCTION Oral squamous cell carcinoma (OSCC) is the predominant malignant neoplasm of the oral cavity followed by verrucous carcinoma, undifferentiated carcinoma, and small salivary adenocarcinoma. 1 Esophageal squamous cell carcinoma (ESCC) is the first histological type and accounts for 80% of cases of esophageal cancer. 2 OSCC and ESCC are indicated as one of the most common cancers by the International Union Against Cancer with an annual incidence of 275 000 and 456 000 cases worldwide, respectively. 3,4 The primary etiology in both OSCC and ESCC is attributed to the environmental factors (tobacco abuse, alcohol consumption), genetic factors (eg, mutations in enzymes), viral factors (human papilloma virus [HPV] infection), and/or the coexistence of these factors. Alcohol intake and tobacco use are responsible for at least 75% of these carcinomas. The underlying initiation and progression mechanisms of OSCC and ESCC are generally characterized by the accumulation of serial epigenetic and genetic alterations, which eventually lead to uncontrolled proliferation of the mutated cells, followed by vigorous cell division. 5,7 Early-stage OSCC detection displays an 80% survival rate at 5 years, while detection at advanced stage leads to survival rates ranging from 20% to 40%. 6 In ESCC, the 5-year survival rate for early-stage detection may reach 85%, whereas a dr...

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Discovery of a small molecule targeting ULK1-modulated cell death of triple negative breast cancer in vitro and in vivo

Abstract: ULK1 is identified as a target in TNBC; thus a small-molecule agonist is discovered by targeting ULK1-modulated cell death, associated with autophagy and apoptosis.

Cited by 129 publications

References 51 publications

A Pan-Cancer assessment of alterations of the kinase domain of ULK1, an upstream regulator of autophagy

A Pan-Cancer assessment of alterations of the kinase domain of ULK1, an upstream regulator of autophagy

Fluoxetine induces autophagic cell death via eEF2K‐AMPK‐mTOR‐ULK complex axis in triple negative breast cancer

Autophagy modulators for the treatment of oral and esophageal squamous cell carcinomas

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