IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling DOI Creative Commons
Xia Sheng, Hatice Zeynep Nenseth, Su Qu

et al.

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Jan. 24, 2019

Abstract Activation of endoplasmic reticulum (ER) stress/the unfolded protein response (UPR) has been linked to cancer, but the molecular mechanisms are poorly understood and there is a paucity reagents translate this for cancer therapy. Here, we report that an IRE1α RNase-specific inhibitor, MKC8866, strongly inhibits prostate (PCa) tumor growth as monotherapy in multiple preclinical models mice shows synergistic antitumor effects with current PCa drugs. Interestingly, global transcriptomic analysis reveal IRE1α-XBP1s pathway activity required c-MYC signaling, one most highly activated oncogenic pathways PCa. XBP1s necessary optimal mRNA expression, establishing, first time, direct link between UPR oncogene activation. In addition, XBP1-specific gene expression signature associated prognosis. Our data establish signaling central indicate its targeting may offer novel treatment strategies.

Language: Английский

Therapeutic target database 2020: enriched resource for facilitating research and early development of targeted therapeutics DOI Creative Commons
Yunxia Wang, Song Zhang, Fengcheng Li

et al.

Nucleic Acids Research, Journal Year: 2019, Volume and Issue: unknown

Published: Oct. 12, 2019

Knowledge of therapeutic targets and early drug candidates is useful for improved discovery. In particular, information about target regulators the patented agents facilitates research regarding druggability, systems pharmacology, new trends, molecular landscapes, development discovery tools. To complement other databases, we constructed Therapeutic Target Database (TTD) with expanded (i) target-regulating microRNAs transcription factors, (ii) target-interacting proteins, (iii) their (structures experimental activity values if available), which can be conveniently retrieved further enriched regulatory mechanisms or biochemical classes. We also updated TTD recently released International Classification Diseases ICD-11 codes additional sets successful, clinical trial, literature-reported that emerged since last update. accessible at http://bidd.nus.edu.sg/group/ttd/ttd.asp. case possible web connectivity issues, two mirror sites are (http://db.idrblab.org/ttd/ http://db.idrblab.net/ttd/).

Language: Английский

Citations

772
KRAS mutation: from undruggable to druggable in cancer DOI Creative Commons

Lamei Huang,

Zhixing Guo, Fang Wang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: Nov. 15, 2021

Abstract Cancer is the leading cause of death worldwide, and its treatment outcomes have been dramatically revolutionised by targeted therapies. As most frequently mutated oncogene, Kirsten rat sarcoma viral oncogene homologue (KRAS) has attracted substantial attention. The understanding KRAS constantly being updated numerous studies on in initiation progression cancer diseases. However, deemed a challenging therapeutic target, even “undruggable”, after drug-targeting efforts over past four decades. Recently, there surprising advances directly drugs for KRAS, especially (G12C) inhibitors, such as AMG510 (sotorasib) MRTX849 (adagrasib), which obtained encouraging results clinical trials. Excitingly, was first to be approved use this year. This review summarises recent fundamental aspects relationship between mutations tumour immune evasion, new progress targeting particularly (G12C). Moreover, possible mechanisms resistance inhibitors combination therapies are summarised, with view providing best regimen individualised achieving truly precise treatment.

Language: Английский

Citations

626
The role of ubiquitination in tumorigenesis and targeted drug discovery DOI Creative Commons
Lu Deng, Tong Meng, Lei Chen

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2020, Volume and Issue: 5(1)

Published: Feb. 29, 2020

Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" "quality" various proteins, serving to ensure cell homeostasis guarantee life activities. The regulation ubiquitination is multifaceted works not only at transcriptional levels (phosphorylation, acetylation, methylation, etc.) but also level (activators or repressors). When regulatory mechanisms are aberrant, altered biological processes may induce serious human diseases, especially types cancer. In tumorigenesis, involve tumor metabolism, immunological microenvironment (TME), cancer stem (CSC) stemness so on. With regard some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc P53 significantly regulates activity mTORC1, AMPK PTEN-AKT signaling pathways. addition, TLR, RLR STING-dependent pathways modulates TME. Moreover, core regulator triplets (Nanog, Oct4 Sox2) members Wnt Hippo-YAP participates maintenance CSC stemness. Based on components, including proteasome, E3 ligases, E1, E2 deubiquitinases (DUBs), many molecular targeted drugs have been developed combat Among them, small molecule inhibitors targeting bortezomib, carfilzomib, oprozomib ixazomib, achieved tangible success. MLN7243 MLN4924 (targeting E1 enzyme), Leucettamol A CC0651 nutlin MI-219 compounds G5 F6 DUB activity) shown potential preclinical treatment. this review, we summarize latest progress understanding substrates for their special functions metabolism regulation, TME modulation maintenance. therapeutic targets reviewed, effects drugs.

Language: Английский

Citations

535
A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo DOI Creative Commons
Longchuan Bai, Haibin Zhou,

Renqi Xu

et al.

Cancer Cell, Journal Year: 2019, Volume and Issue: 36(5), P. 498 - 511.e17

Published: Nov. 1, 2019

Language: Английский

Citations

492
Integrative Proteomic Characterization of Human Lung Adenocarcinoma DOI Creative Commons
Jun‐Yu Xu, Chunchao Zhang, Xiang Wang

et al.

Cell, Journal Year: 2020, Volume and Issue: 182(1), P. 245 - 261.e17

Published: July 1, 2020

Language: Английский

Citations

461
Small molecules, big impact: 20 years of targeted therapy in oncology DOI
Philippe L. Bédard, David M. Hyman, Matthew S. Davids

et al.

The Lancet, Journal Year: 2020, Volume and Issue: 395(10229), P. 1078 - 1088

Published: March 1, 2020

Language: Английский

Citations

459
Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN DOI Open Access
Quinlan Sievers, Georg Petzold, R.D. Bunker

et al.

Science, Journal Year: 2018, Volume and Issue: 362(6414)

Published: Nov. 1, 2018

Thalidomide-targeted degradation Thalidomide and its analogs improve the survival of patients with multiple myeloma other blood cancers. Previous work showed that drugs bind to E3 ubiquitin ligase Cereblon, which then targets for two specific zinc finger (ZF) transcription factors a role in cancer development. Sievers et al. found more ZF proteins than anticipated are destabilized by thalidomide analogs. A proof-of-concept experiment revealed chemical modifications can lead selective proteins. The detailed information provided structural, biochemical, computational analyses could guide development target implicated human disease. Science , this issue p. eaat0572

Language: Английский

Citations

418
Targeting RNA structures with small molecules DOI Open Access
Jessica L. Childs‐Disney, Xueyi Yang, Quentin M. R. Gibaut

et al.

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(10), P. 736 - 762

Published: Aug. 8, 2022

Language: Английский

Citations

357
Taking the Myc out of cancer: toward therapeutic strategies to directly inhibit c-Myc DOI Creative Commons
Sarah K. Madden, Aline D. de Araujo,

Mara Gerhardt

et al.

Molecular Cancer, Journal Year: 2021, Volume and Issue: 20(1)

Published: Jan. 4, 2021

c-Myc is a transcription factor that constitutively and aberrantly expressed in over 70% of human cancers. Its direct inhibition has been shown to trigger rapid tumor regression mice with only mild fully reversible side effects, suggesting this be viable therapeutic strategy. Here we reassess the challenges directly targeting c-Myc, evaluate lessons learned from current inhibitors, explore how future strategies such as miniaturisation Omomyc E-box binding could facilitate translation inhibitors into clinic.

Language: Английский

Citations

310
Overcoming Endosomal Entrapment in Drug Delivery DOI
Dehua Pei, Marina Buyanova

Bioconjugate Chemistry, Journal Year: 2018, Volume and Issue: 30(2), P. 273 - 283

Published: Dec. 10, 2018

Intracellular delivery of biological agents such as peptides, proteins, and nucleic acids generally rely on the endocytic pathway major uptake mechanism, resulting in their entrapment inside endosome lysosome. The recent discovery cell-penetrating molecules exceptionally high endosomal escape cytosolic efficiencies elucidation mechanism action represent breakthroughs this field. In Topical Review, we provide an overview progress understanding enhancing process new opportunities opened up by these findings.

Language: Английский

Citations

295