bims-pimaco 2023-09-03 papers

Issue of 2023‒09‒03
two papers selected by
Lucas B. Zeiger, Beatson Institute for Cancer Research

Nat Struct Mol Biol. 2023 Aug 28.

Excited-state observation of active K-Ras reveals differential structural dynamics of wild-type versus oncogenic G12D and G12C mutants.

Alexandar L Hansen, Xinyao Xiang, Chunhua Yuan, Lei Bruschweiler-Li, Rafael Brüschweiler.

Despite the prominent role of the K-Ras protein in many different types of human cancer, major gaps in atomic-level information severely limit our understanding of its functions in health and disease. Here, we report the quantitative backbone structural dynamics of K-Ras by solution nuclear magnetic resonance spectroscopy of the active state of wild-type K-Ras bound to guanosine triphosphate (GTP) nucleotide and two of its oncogenic P-loop mutants, G12D and G12C, using a new nanoparticle-assisted spin relaxation method, relaxation dispersion and chemical exchange saturation transfer experiments covering the entire range of timescales from picoseconds to milliseconds. Our combined experiments allow detection and analysis of the functionally critical Switch I and Switch II regions, which have previously remained largely unobservable by X-ray crystallography and nuclear magnetic resonance spectroscopy. Our data reveal cooperative transitions of K-Ras·GTP to a highly dynamic excited state that closely resembles the partially disordered K-Ras·GDP state. These results advance our understanding of differential GTPase activities and signaling properties of the wild type versus mutants and may thus guide new strategies for the development of therapeutics.

DOI: https://doi.org/10.1038/s41594-023-01070-z

Eur J Med Chem. 2023 Aug 24. pii: S0223-5234(23)00721-3. [Epub ahead of print]260 115754

Design, synthesis and bioevaluation of PI3Kα-selective inhibitors as potential colorectal cancer drugs.

Xue-Mei Zheng, Yuan-Si Chen, Yu-Juan Ban, Yu-Jie Wang, Yong-Xi Dong, Li Lei, Bing Guo, Jian-Ta Wang, Lei Tang, Hong-Liang Li, Ji-Quan Zhang.

The dysregulation of the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin signaling pathway has been implicated in various human cancers, and isoform-selective inhibitors targeting PI3Kα have received significant interest in recent years. In this study, we have designed and synthesized three series of substituted benzoxazole derivatives based on the clinical candidate TAK-117 (8a). A detailed structure-activity relationship (SAR) study has identified the optimal compound 18a bearing a quinoxaline scaffold. Compared to the control 8a, 18a exhibited 4.4-fold more potent inhibitory activity against PI3Kα (IC50: 2.5 vs 11 nM) and better isoform-selective profiles over other PI3Ks. In addition, 18a showed a 1.5-fold more potent antiproliferative effect against HCT-116 cell lines (IC50: 3.79 vs 5.80 μM) and a better selectivity over the normal tissue cells. The potential antitumor mechanism and in vitro metabolic stability of 18a were also investigated. Notably, pharmacokinetic assays indicated that 18a had a higher plasma exposure, a higher maximum concentration and shorter elimination time compared to 8a.

Keywords: Isoform-selective; Kinase inhibitor; Phosphoinositide 3-kinase; Structure–activity relationship; Synthesis

DOI: https://doi.org/10.1016/j.ejmech.2023.115754