Targeting small GTPases: emerging grasps on previously untamable targets, pioneered by KRAS

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

Published: May 23, 2023

Small GTPases including Ras, Rho, Rab, Arf, and Ran are omnipresent molecular switches in regulating key cellular functions. Their dysregulation is a therapeutic target for tumors, neurodegeneration, cardiomyopathies, infection. However, small have been historically recognized as "undruggable". Targeting KRAS, one of the most frequently mutated oncogenes, has only come into reality last decade due to development breakthrough strategies such fragment-based screening, covalent ligands, macromolecule inhibitors, PROTACs. Two KRASG12C inhibitors obtained accelerated approval treating mutant lung cancer, allele-specific hotspot mutations on G12D/S/R demonstrated viable targets. New methods targeting KRAS quickly evolving, transcription, immunogenic neoepitopes, combinatory with immunotherapy. Nevertheless, vast majority remain elusive, clinical resistance G12C poses new challenges. In this article, we summarize diversified biological functions, shared structural properties, complex regulatory mechanisms their relationships human diseases. Furthermore, review status drug discovery recent strategic progress focused KRAS. The approaches will together promote GTPases.

Language: Английский

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Advances and Prospects in the Treatment of Pancreatic Cancer

International Journal of Nanomedicine, Journal Year: 2023, Volume and Issue: Volume 18, P. 3973 - 3988

Published: July 1, 2023

Abstract: Pancreatic cancer is a highly malignant and incurable disease, characterized by its aggressive nature high fatality rate. The most common type pancreatic ductal adenocarcinoma (PDAC), which has poor prognosis mortality Current treatments for mainly encompass surgery, chemotherapy, radiotherapy, targeted therapy, combination regimens. However, despite efforts to improve prognosis, the 5-year survival rate remains very low. Therefore, it's urgent explore novel therapeutic approaches. With rapid development of strategies in recent years, new ideas have been provided treating cancer. This review expositions advancements nano drug delivery system, molecular drugs, photo-thermal treatment combined with nanotechnology It comprehensively analyzes prospects cancer, aiming at deeper understanding existing drugs approaches, promoting attempting enhance effect patients this disease. Keywords:

Language: Английский

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A landscape of response to drug combinations in non-small cell lung cancer

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 28, 2023

Abstract Combination of anti-cancer drugs is broadly seen as way to overcome the often-limited efficacy single agents. The design and testing combinations are however very challenging. Here we present a uniquely large dataset screening over 5000 targeted agent across 81 non-small cell lung cancer lines. Our analysis reveals profound heterogeneity response tumor models. Notably, rarely result in strong gain range observable with Importantly, activity agents more often when co-targeting functionally proximal genes, offering strategy for designing efficient combinations. Because combinatorial effect strongly context specific, specificity should be achievable. resource provided, together an additional validation screen sheds light on major challenges opportunities building efficacious against provides opportunity training computational models synergy prediction.

Language: Английский

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A hybrid deep forest-based method for predicting synergistic drug combinations

Cell Reports Methods, Journal Year: 2023, Volume and Issue: 3(2), P. 100411 - 100411

Published: Feb. 1, 2023

Combination therapy is a promising approach in treating multiple complex diseases. However, the large search space of available drug combinations exacerbates challenge for experimental screening. To predict synergistic different cancer cell lines, we propose an improved deep forest-based method, ForSyn, and design two forest types embedded ForSyn. ForSyn handles imbalanced high-dimensional data medium-/small-scale datasets, which are inherent characteristics combination datasets. Compared with 12 state-of-the-art methods, ranks first on four metrics eight datasets feature combinations. We conduct systematic analysis to identify most appropriate configuration parameters. validate predictive value cell-based experiments several previously unexplored Finally, importance performed top contributing features extracted by The resulting key genes may play roles corresponding cancers.

Language: Английский

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Priority control sequence of 34 typical pollutants in effluents of Chinese wastewater treatment plants

Water Research, Journal Year: 2023, Volume and Issue: 243, P. 120338 - 120338

Published: July 11, 2023

Language: Английский

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