Category Ranking
98%
Total Visits
921
Avg Visit Duration
2 minutes
Citations
20
Article Abstract
Src homology-2-containing protein tyrosine phosphatase (PTP) 2 (SHP2) is a pivotal PTP that modulates key cellular processes including proliferation, differentiation, and migration. Its overexpression is implicated in the pathogenesis of various malignancies, highlighting the need for effective SHP2 inhibitors. Herein, we report the design and synthesis of a novel series of thiazolo[5,4-]pyridine and imidazo[1,2-]pyrimidine derivatives as SHP2 allosteric inhibitors identified through active fragment splicing. The synthesized compounds exhibited potent SHP2 inhibition, with IC values ranging from 9.0 to 34.5 nM. Notably, compound demonstrated superior potency, with an IC of 0.04 μM for p-ERK modulation. Compound also displayed favorable drug-like properties and significant antitumor activity in a KYSE520 xenograft mouse model, underscoring its potential as a lead candidate for further development. Our findings provide a foundation for the advancement of SHP2-targeted therapeutics.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/acs.jmedchem.4c02100 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Another Slice of the Pie Uncovered: RIT1M90I Is an Actionable Driver in Non-Small Cell Lung Cancer.
Cancer Res
September 2025
Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas.
Lung adenocarcinoma has become a paradigm for precision oncology and success with targeted therapies. However, large chunks of the pie chart of molecular drivers remain unknown, preventing many patients from similarly benefiting from this strategy. Here, we highlight the side-by-side release of two impactful studies from Mozzarelli and colleagues and DiMarco and colleagues in this issue of Cancer Research.
View Article and Find Full Text PDFNovel azabicyclic series of potent SHP2 allosteric inhibitors.
Bioorg Med Chem Lett
August 2025
Department of Drug Discovery, IRBM S.p.A., 00071 Pomezia, Rome, Italy.
The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, is a critical component of the RAS/RAF/MEK/ERK signaling pathway, functioning upstream of RAS to promote oncogenic signaling and tumor growth. As part of a drug discovery program aimed at obtaining novel allosteric SHP2 inhibitors, a series of original azabicyclic compounds was identified. Extensive preliminary SAR around the novel bicyclic basic moiety (left-hand side) and the heteroaryl portion (right-hand side) yielded a highly potent series of SHP2 inhibitors with demonstrated cellular potency (pERK inhibition, as downstream marker of MAPK pathway activity) as well as antiproliferative activity in a KYSE-520 cancer cell line.
View Article and Find Full Text PDFSubstituted 1,4-naphthoquinones for potential anticancer therapeutics: cytotoxic effects and QSAR-guided design of new analogs.
Comput Struct Biotechnol J
July 2025
Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
1,4-Naphthoquinone is a promising pharmacophore in drug discovery due to its unique redox reactive nature and wide-ranging bioactivities. Herein, a series of 1,4-naphthoquinones (-) were investigated for their anticancer activities against 4 cancer cell lines (i.e.
View Article and Find Full Text PDFStructure-guided expansion strategy unveils potent allosteric SHP2 inhibitors with synergistic efficacy against AML through MCL-1 co-targeting.
Eur J Med Chem
November 2025
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China; State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address:
SHP2, an oncogenic phosphatase pivotal in RAS-MAPK, PI3K-AKT, and JAK-STAT signaling, represents a compelling therapeutic target in malignancies driven by its hyperactivation. While allosteric inhibitors like SHP099 have overcome historical challenges of orthosteric agents by stabilizing SHP2's autoinhibited conformation, opportunities remain to enhance potency, selectivity, and clinical utility. Here, we report a structure-guided expansion strategy leveraging detailed profiling of the tunnel-shaped allosteric pocket to design next-generation inhibitors.
View Article and Find Full Text PDFDiscovery of SA-8 as a potent SHP2-AUTAC degrader in cancer therapy.
Eur J Med Chem
November 2025
Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; Institute of Structural Pharmacology & TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medici
Src homology region 2-containing phosphatase 2 (SHP2) is overexpressed in various cancers and suppresses immune function while promoting tumor immune escape by regulating intracellular signaling pathways. Currently, the primary therapeutic strategies targeting SHP2 focus on inhibiting its catalytic activity or reducing its expression levels. However, SHP2 allosteric inhibitors face challenges in terms of efficacy, safety, and developmental difficulty when used as monotherapy.
View Article and Find Full Text PDF