Mechanisms and biotechnological applications of transcription factors DOI Creative Commons

Hehe He,

Yang Mingfei,

Siyu Li

et al.

Synthetic and Systems Biotechnology, Journal Year: 2023, Volume and Issue: 8(4), P. 565 - 577

Published: Aug. 31, 2023

Transcription factors play an indispensable role in maintaining cellular viability and finely regulating complex internal metabolic networks. These crucial bioactive functions rely on their ability to respond effectors concurrently interact with binding sites. Recent advancements have brought innovative insights into the understanding of transcription factors. In this review, we comprehensively summarize mechanisms by which carry out functions, along calculation experimental-based methods employed identification. Additionally, highlight recent achievements application various biotechnological fields, including cell engineering, human health, biomanufacturing. Finally, current limitations research provide prospects for future investigations are discussed. This review will enlightening theoretical guidance engineering.

Language: Английский

Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials DOI Creative Commons
Xin Xie, Tingting Yu, Xiang Li

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 6, 2023

Abstract Undruggable proteins are a class of that often characterized by large, complex structures or functions difficult to interfere with using conventional drug design strategies. Targeting such undruggable targets has been considered also great opportunity for treatment human diseases and attracted substantial efforts in the field medicine. Therefore, this review, we focus on recent development discovery targeting “undruggable” their application clinic. To make review well organized, discuss strategies proteins, including covalent regulation, allosteric inhibition, protein–protein/DNA interaction targeted nucleic acid-based approach, immunotherapy others.

Language: Английский

Citations

175
Targeting androgen receptor phase separation to overcome antiandrogen resistance DOI
Jingjing Xie, Hao He,

Wenna Kong

et al.

Nature Chemical Biology, Journal Year: 2022, Volume and Issue: 18(12), P. 1341 - 1350

Published: Oct. 13, 2022

Language: Английский

Citations

100
FOXO transcription factors as therapeutic targets in human diseases DOI Creative Commons
Alba Orea-Soufi, Jihye Paik, José Bragança

et al.

Trends in Pharmacological Sciences, Journal Year: 2022, Volume and Issue: 43(12), P. 1070 - 1084

Published: Oct. 21, 2022

Language: Английский

Citations

98
Small molecules in the treatment of COVID-19 DOI Creative Commons
Sibei Lei, Xiaohua Chen, Jieping Wu

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Dec. 5, 2022

Abstract The outbreak of COVID-19 has become a global crisis, and brought severe disruptions to societies economies. Until now, effective therapeutics against are in high demand. Along with our improved understanding the structure, function, pathogenic process SARS-CoV-2, many small molecules potential anti-COVID-19 effects have been developed. So far, several antiviral strategies were explored. Besides directly inhibition viral proteins such as RdRp M pro , interference host enzymes including ACE2 proteases, blocking relevant immunoregulatory pathways represented by JAK/STAT, BTK, NF-κB, NLRP3 pathways, regarded feasible drug development. development treat achieved strategies, computer-aided lead compound design screening, natural product discovery, repurposing, combination therapy. Several representative remdesivir paxlovid proved or authorized emergency use countries. And candidates entered clinical-trial stage. Nevertheless, due epidemiological features variability issues it is necessary continue exploring novel COVID-19. This review discusses current findings for treatment. Moreover, their detailed mechanism action, chemical structures, preclinical clinical efficacies discussed.

Language: Английский

Citations

85
c-Myc-Targeting PROTAC Based on a TNA-DNA Bivalent Binder for Combination Therapy of Triple-Negative Breast Cancer DOI
Xintong Li, Ze Zhang,

Fangyan Gao

et al.

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(16), P. 9334 - 9342

Published: April 17, 2023

Triple-negative breast cancer (TNBC) is highly aggressive with a poor clinical prognosis and no targeted therapy. The c-Myc protein master transcription factor potential therapeutic target for TNBC. In this study, we develop PROTAC (PROteolysis TArgeting Chimera) based on TNA (threose nucleic acid) DNA that effectively targets degrades c-Myc. aptamer selected in vitro to bind the c-Myc/Max heterodimer appended E-box sequence create high-affinity, biologically stable bivalent binder. TNA-E box-pomalidomide (TEP) conjugate specifically endogenous c-Myc/Max, inhibits TNBC cell proliferation, sensitizes cells cyclin-dependent kinase inhibitor palbociclib vitro. mouse model, combination therapy TEP potently suppresses tumor growth. This study offers promising acid-based modality both chemical biology studies interventions of

Language: Английский

Citations

72
Novel cancer treatment paradigm targeting hypoxia-induced factor in conjunction with current therapies to overcome resistance DOI Creative Commons
Ting‐Wan Kao, Geng-Hao Bai, Tian‐Li Wang

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 42(1)

Published: July 18, 2023

Chemotherapy, radiotherapy, targeted therapy, and immunotherapy are established cancer treatment modalities that widely used due to their demonstrated efficacy against tumors favorable safety profiles or tolerability. Nevertheless, resistance continues be one of the most pressing unsolved conundrums in treatment. Hypoxia-inducible factors (HIFs) a family transcription regulate cellular responses hypoxia by activating genes involved various adaptations, including erythropoiesis, glucose metabolism, angiogenesis, cell proliferation, apoptosis. Despite this critical function, overexpression HIFs has been observed numerous cancers, leading therapy disease progression. In recent years, much effort poured into developing innovative treatments target HIF pathway. Combining inhibitors with current therapies increase anti-tumor activity diminish is strategy for combating therapeutic resistance. This review focuses on how could applied conjunction treatments, those now being evaluated clinical trials, usher new era therapy.

Language: Английский

Citations

47
A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction DOI
Pamela Y. Ting, Sneha Borikar,

John Ryan Kerrigan

et al.

Science, Journal Year: 2024, Volume and Issue: 385(6704), P. 91 - 99

Published: July 4, 2024

Sickle cell disease (SCD) is a prevalent, life-threatening condition attributable to heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) can ameliorate complications and has been intently pursued. However, safe effective small-molecule inducers HbF remain elusive. We report the discovery dWIZ-1 dWIZ-2, molecular glue degraders WIZ transcription factor that robustly induce erythroblasts. Phenotypic screening cereblon (CRBN)-biased chemical library revealed as previously unknown repressor HbF. degradation mediated by recruitment WIZ(ZF7) CRBN dWIZ-1, resolved crystallography ternary complex. Pharmacological was well tolerated induced humanized mice cynomolgus monkeys. These findings establish globally accessible therapeutic strategy for SCD.

Language: Английский

Citations

23
Targeting the undruggables—the power of protein degraders DOI Creative Commons
Chao Zhang, Yongbo Liu, Guangchen Li

et al.

Science Bulletin, Journal Year: 2024, Volume and Issue: 69(11), P. 1776 - 1797

Published: March 29, 2024

Undruggable targets typically refer to a class of therapeutic that are difficult target through conventional methods or have not yet been targeted, but great clinical significance. According statistics, over 80% disease-related pathogenic proteins cannot be targeted by current treatment methods. In recent years, with the advancement basic research and new technologies, development various technologies mechanisms has brought perspectives overcome challenging drug targets. Among them, protein degradation technology is breakthrough strategy for This can specifically identify directly degrade utilizing inherent pathways within cells. form includes types such as proteolysis targeting chimera (PROTAC), molecular glue, lysosome-targeting Chimaera (LYTAC), autophagosome-tethering compound (ATTEC), autophagy-targeting (AUTAC), (AUTOTAC), degrader-antibody conjugate (DAC). article systematically summarizes application in degraders Finally, looks forward future direction prospects technology.

Language: Английский

Citations

22
Macrocycles and macrocyclization in anticancer drug discovery: Important pieces of the puzzle DOI
Chao Zhang,

Fenfen Liu,

You‐Ming Zhang

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 268, P. 116234 - 116234

Published: Feb. 13, 2024

Language: Английский

Citations

20
Pioneer factor GATA6 promotes colorectal cancer through 3D genome regulation DOI Creative Commons
Huijue Lyu, X.-X. Chen,

Yang Cheng

et al.

Science Advances, Journal Year: 2025, Volume and Issue: 11(6)

Published: Feb. 7, 2025

Colorectal cancer (CRC) is one of the most lethal and prevalent malignancies. While overexpression pioneer factor GATA6 in CRC has been linked with metastasis, its role genome-wide gene expression dysregulation remains unclear. Through studies primary human tissues analysis TCGA data, we found that preferentially binds at CRC-specific active enhancers, enrichment enhancer-promoter loop anchors. protein also physically interacts CTCF, suggesting critical 3D genome organization. The ablation through AID CRISPR systems severely impaired cell clonogenicity proliferation. Mechanistically, knockout induced global loss open chromatins extensive alterations interactions for oncogenes. Last, showed greatly reduced tumor growth improved survival mice. Together, revealed a previously unidentified mechanism by which contributes to pathogenesis colorectal cancer.

Language: Английский

Citations

3