bims-sikglu 2024-09-01 papers

Issue of 2024‒09‒01
two papers selected by
Dipsikha Biswas, Københavns Universitet and Maria Madrazo i Montoya, Københavns Universitet

Int J Mol Sci. 2024 Aug 10. pii: 8731. [Epub ahead of print]25(16):

Pathophysiological Relationship between Type 2 Diabetes Mellitus and Metabolic Dysfunction-Associated Steatotic Liver Disease: Novel Therapeutic Approaches.

Shifat-E Ferdous, Jessica M Ferrell.

Type 2 diabetes mellitus (T2DM), often featuring hyperglycemia or insulin resistance, is a global health concern that is increasing in prevalence in the United States and worldwide. A common complication is metabolic dysfunction-associated steatotic liver disease (MASLD), the hepatic manifestation of metabolic syndrome that is also rapidly increasing in prevalence. The majority of patients with T2DM will experience MASLD, and likewise, individuals with MASLD are at an increased risk for developing T2DM. These two disorders may act synergistically, in part due to increased lipotoxicity and inflammation within the liver, among other causes. However, the pathophysiological mechanisms by which this occurs are unclear, as is how the improvement of one disorder can ameliorate the other. This review aims to discuss the pathogenic interactions between T2D and MASLD, and will highlight novel therapeutic targets and ongoing clinical trials for the treatment of these diseases.

Keywords: MASLD; hyperglycemia; liver disease; metabolic disease; steatosis

DOI: https://doi.org/10.3390/ijms25168731

Chem Sci. 2024 Aug 22. 15(33): 13130-13147

The prospect of substrate-based kinase inhibitors to improve target selectivity and overcome drug resistance.

Biswajit Biswas, Yen-Hua Huang, David J Craik, Conan K Wang.

Human kinases are recognized as one of the most important drug targets associated with cancer. There are >80 FDA-approved kinase inhibitors to date, most of which work by inhibiting ATP binding to the kinase. However, the frequent development of single-point mutations within the kinase domain has made overcoming drug resistance a major challenge in drug discovery today. Targeting the substrate site of kinases can offer a more selective and resistance-resilient solution compared to ATP inhibition but has traditionally been challenging. However, emerging technologies for the discovery of drug leads using recombinant display and stabilization of lead compounds have increased interest in targeting the substrate site of kinases. This review discusses recent advances in the substrate-based inhibition of protein kinases and the potential of such approaches for overcoming the emergence of resistance.

DOI: https://doi.org/10.1039/d4sc01088d