Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Сен. 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.

Язык: Английский

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Targeting androgen receptor phase separation to overcome antiandrogen resistance

Nature Chemical Biology, Год журнала: 2022, Номер 18(12), С. 1341 - 1350

Опубликована: Окт. 13, 2022

Язык: Английский

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FOXO transcription factors as therapeutic targets in human diseases

Trends in Pharmacological Sciences, Год журнала: 2022, Номер 43(12), С. 1070 - 1084

Опубликована: Окт. 21, 2022

Язык: Английский

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Small molecules in the treatment of COVID-19

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Дек. 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.

Язык: Английский

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c-Myc-Targeting PROTAC Based on a TNA-DNA Bivalent Binder for Combination Therapy of Triple-Negative Breast Cancer

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(16), С. 9334 - 9342

Опубликована: Апрель 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

Язык: Английский

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Novel cancer treatment paradigm targeting hypoxia-induced factor in conjunction with current therapies to overcome resistance

Journal of Experimental & Clinical Cancer Research, Год журнала: 2023, Номер 42(1)

Опубликована: Июль 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.

Язык: Английский

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Macrocycles and macrocyclization in anticancer drug discovery: Important pieces of the puzzle

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 268, С. 116234 - 116234

Опубликована: Фев. 13, 2024

Язык: Английский

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Targeting the undruggables—the power of protein degraders

Science Bulletin, Год журнала: 2024, Номер 69(11), С. 1776 - 1797

Опубликована: Март 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.

Язык: Английский

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A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction

Science, Год журнала: 2024, Номер 385(6704), С. 91 - 99

Опубликована: Июль 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.

Язык: Английский

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Single-cell and bulk transcriptomics of the liver reveals potential targets of NASH with fibrosis

Scientific Reports, Год журнала: 2021, Номер 11(1)

Опубликована: Сен. 29, 2021

Abstract Fibrosis is characterized by the excessive production of collagen and other extracellular matrix (ECM) components represents a leading cause morbidity mortality worldwide. Previous studies nonalcoholic steatohepatitis (NASH) with fibrosis were largely restricted to bulk transcriptome profiles. Thus, our understanding this disease limited an incomplete characterization liver cell types in general hepatic stellate cells (HSCs) particular, given that activated HSCs are major fibrogenic population. To help fill gap, we profiled 17,810 non-parenchymal derived from six healthy human livers. In conjunction public single-cell data fibrotic/cirrhotic livers, these profiles enable identification potential intercellular signaling axes (e.g., ITGAV–LAMC1, TNFRSF11B–VWF NOTCH2–DLL4) master regulators RUNX1 CREB3L1 ) responsible for activation during fibrogenesis. Bulk RNA-seq NASH patient livers rodent models diverse etiologies allowed us evaluate translatability candidate therapeutic targets NASH-related fibrosis. We identified 61 fibrosis-associated genes AEBP1, PRRX1 LARP6 may serve as repertoire translatable drug target candidates. Consistent above regulon results, gene regulatory network analysis regulator many genes. Together, study highlights cell–cell interactions underlie HSC reveals represent prospective hallmark signatures

Язык: Английский

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