Molecular Glue-Mediated Targeted Protein Degradation: A Novel Strategy in Small-Molecule Drug Development DOI Creative Commons
Xueqiang Tan, Zuyi Huang, Hairun Pei

et al.

iScience, Journal Year: 2024, Volume and Issue: 27(9), P. 110712 - 110712

Published: Aug. 23, 2024

Small-molecule drugs are effective and thus most widely used. However, their applications limited by reliance on active high-affinity binding sites, restricting target options. A breakthrough approach involves molecular glues, a novel class of small-molecule compounds capable inducing protein-protein interactions (PPIs). This opens avenues to conventionally undruggable proteins, overcoming limitations seen in conventional drugs. Molecular glues play key role targeted protein degradation (TPD) techniques, including ubiquitin-proteasome system-based approaches such as proteolysis targeting chimeras (PROTACs) glue degraders recently emergent lysosome techniques like extracellular proteins through the asialoglycoprotein receptors (MoDE-As) macroautophagy (MADTACs). These enable an innovative strategy for prolonged inhibition pathology-associated proteins. review provides overview them, emphasizing clinical potential guiding development molecular-glue-mediated TPD techniques.

Language: Английский

Structure–Activity Relationship Study and Design Strategies of Hydantoin, Thiazolidinedione, and Rhodanine-Based Kinase Inhibitors: A Two-Decade Review DOI Creative Commons
Muhammad Naufal, Elvira Hermawati, Yana Maolana Syah

et al.

ACS Omega, Journal Year: 2024, Volume and Issue: 9(4), P. 4186 - 4209

Published: Jan. 19, 2024

Cancer is one of the most prominent causes rapidly growing mortality numbers worldwide. originates from normal cells that have acquired capability to alter their molecular, biochemical, and cellular traits. The alteration cell signaling enzymes, such as kinases, can initiate amplify cancer progression. As a curative method, targeted therapy utilized small molecules' inhibit kinase's function. This review provides brief history (1999–2023) Small Molecule Kinase Inhibitors (SMKIs) discovery with molecular perspective. Furthermore, this current also addresses application development hydantoin, thiazolidinedione, rhodanine-based derivatives kinase inhibitors toward several subclasses (EGFR, PI3K, VEGFR, Pim, c-Met, CDK, IGFR, ERK) accompanied by structure–activity relationship study interactions. present work summarizes compiles all important structural information essential for developing improve potency in future.

Language: Английский

Citations

8
Targeted protein degradation using chimeric human E2 ubiquitin-conjugating enzymes DOI Creative Commons
Jonathan D. Taylor,

Nathalie Barrett,

Sergio Martínez Cuesta

et al.

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: Sept. 19, 2024

Language: Английский

Citations

8
Exploration of the Tunability of BRD4 Degradation by DCAF16 Trans-labelling Covalent Glues DOI Creative Commons
Muhammad Murtaza Hassan, Yen-Der Li, W Michelle

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 279, P. 116904 - 116904

Published: Sept. 24, 2024

Language: Английский

Citations

8
Oncogenic STAT Transcription Factors as Targets for Cancer Therapy: Innovative Strategies and Clinical Translation DOI Open Access
Weiyuan Wang,

Melanie Cristina Lopez McDonald,

Rajashree Hariprasad

et al.

Cancers, Journal Year: 2024, Volume and Issue: 16(7), P. 1387 - 1387

Published: March 31, 2024

Despite advances in our understanding of molecular aspects oncogenesis, cancer remains a leading cause death. The malignant behavior cell is driven by the inappropriate activation transcription factors. In particular, signal transducers and activators (STATs), which regulate many critical cellular processes such as proliferation, apoptosis, differentiation, are frequently activated inappropriately wide spectrum human cancers. Multiple signaling pathways converge on STATs, highlighting their importance development progression oncogenic diseases. STAT3 STAT5 two members STAT protein family that most cancers can drive pathogenesis directly. inhibitors targeting has been subject intense investigations last decade, although effective treatment options remain limited. this review, we investigate specific roles normal physiology biology, discuss opportunities challenges pharmacologically proteins upstream activators, offer insights into novel therapeutic strategies to identify therapeutics.

Language: Английский

Citations

7
Molecular Glue-Mediated Targeted Protein Degradation: A Novel Strategy in Small-Molecule Drug Development DOI Creative Commons
Xueqiang Tan, Zuyi Huang, Hairun Pei

et al.

iScience, Journal Year: 2024, Volume and Issue: 27(9), P. 110712 - 110712

Published: Aug. 23, 2024

Small-molecule drugs are effective and thus most widely used. However, their applications limited by reliance on active high-affinity binding sites, restricting target options. A breakthrough approach involves molecular glues, a novel class of small-molecule compounds capable inducing protein-protein interactions (PPIs). This opens avenues to conventionally undruggable proteins, overcoming limitations seen in conventional drugs. Molecular glues play key role targeted protein degradation (TPD) techniques, including ubiquitin-proteasome system-based approaches such as proteolysis targeting chimeras (PROTACs) glue degraders recently emergent lysosome techniques like extracellular proteins through the asialoglycoprotein receptors (MoDE-As) macroautophagy (MADTACs). These enable an innovative strategy for prolonged inhibition pathology-associated proteins. review provides overview them, emphasizing clinical potential guiding development molecular-glue-mediated TPD techniques.

Language: Английский

Citations

7