AI Article Synopsis
- - High levels or mutations of SHP2 are linked to cancer, prompting researchers to target it as a potential treatment strategy, leading to the development of a new SHP2 inhibitor.
- - The synthesized compound 4b showed impressive selectivity and potency as an allosteric inhibitor of SHP2, significantly outperforming the previous standard, IACS-13909, in reducing cancer cell proliferation.
- - Compound 4b demonstrated strong effectiveness against KRAS-mutant lung cancer cells when combined with the KRAS inhibitor sotorasib, suggesting a promising synergy in cancer treatment approaches.
Article Abstract
The high expression or mutation of SHP2 can induce cancer, so targeting SHP2 has become a new strategy for cancer treatment. In this study, we used the previously reported SHP2 allosteric inhibitor IACS-13909 as a lead drug for structural derivation and modification, and synthesized three SHP2 inhibitors. Among them, 1-pyrazolo[3,4-]pyrazine derivative 4b was a highly selective SHP2 allosteric inhibitor, with an IC value of 3.2 nM, and its inhibitory activity was 17.75 times than that of the positive control IACS-13909. The cell proliferation experiment detected that compound 4b would markedly inhibit the proliferation of various cancer cells. Interestingly, compound 4b was highly sensitive to KRAS-mutant non-small cell lung cancer NCI-H358 cells, with an IC value of 0.58 μM and its antiproliferative activity was 4.79 times than that of IACS-13909. Furthermore, the combination therapy of compound 4b and KRAS inhibitor sotorasib would play a strong synergistic effect against NCI-H358 cells. The western blot experiment detected that compound 4b markedly downregulated the phosphorylation levels of ERK and AKT in NCI-H358 cells. Molecular docking study predicted that compound 4b bound to the allosteric site of SHP2 and formed H-bond interactions with key residues Thr108, Glu110, Arg111, and Phe113. In summary, this study aims to provide new ideas for the development of SHP2 allosteric inhibitors for the treatment of KRAS mutant non-small cell lung cancer.Communicated by Ramaswamy H. Sarma.
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| http://dx.doi.org/10.1080/07391102.2024.2308771 | DOI Listing |
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