PCC0208023, a potent SHP2 allosteric inhibitor, imparts an antitumor effect against KRAS mutant colorectal cancer
| Autor: | Zhengping Hu, Liang Ye, Pengfei Yu, Jingwei Tian, Hongbo Wang, Fangxia Zou, Wenyan Wang, Xiao Chen, Guangying Du |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Colorectal cancer MAP Kinase Signaling System Allosteric regulation Mice Nude Antineoplastic Agents Protein Tyrosine Phosphatase Non-Receptor Type 11 Toxicology medicine.disease_cause Proto-Oncogene Proteins p21(ras) 03 medical and health sciences Mice 0302 clinical medicine In vivo Cell Line Tumor medicine Animals Humans Protein Kinase Inhibitors Cell Proliferation Pharmacology chemistry.chemical_classification Mitogen-Activated Protein Kinase Kinases Mice Inbred BALB C Chemistry medicine.disease HCT116 Cells Xenograft Model Antitumor Assays In vitro PTPN11 030104 developmental biology Enzyme 030220 oncology & carcinogenesis Mutation Cancer research Female KRAS Colorectal Neoplasms Signal Transduction |
| Zdroj: | Toxicology and applied pharmacology. 398 |
| ISSN: | 1096-0333 |
| Popis: | The non-receptor tyrosine phosphatase SHP2, encoded by PTPN11, plays an indispensable role in tumors driven by oncogenic KRAS mutations, which frequently occur in colorectal cancer. Here, PCC0208023, a potent SHP2 allosteric inhibitor, was synthesized to evaluate its inhibitory effects against the SHP2 enzyme, and the KRAS mutant colorectal cancer in vitro and in vivo, and its impart on the RAS/MAPK pathway. Consistent with an allosteric mode of inhibition, PCC0208023 can non-competitively inhibit the activity of full-length SHP2 enzyme, but lacks activity against the free catalytic domain of SHP2. Furthermore, PCC0208023 inhibited the proliferation of KRAS mutation-driven human colorectal cancer cells by inhibiting the RAS/MAPK signaling pathway in vitro. Importantly, PCC0208023 displayed good anti-tumor efficacy against KRAS-driven LS180 and HCT116 xenograft models in nude mice with the decreased Ki67 and p-ERK level, and increased cleaved caspase-3 expression in tumors. Interestingly, PCC0208023 maintained high levels in LS180 tumors within 24 h after administration and was mainly distributed in both intestines and lungs. Molecular docking studies revealed a higher affinity of PCC0208023 with key residues in the SHP2 allosteric pocket than RMC-4550. PCC0208023 deserves further optimization to identify additional low-toxic and potent SHP2 allosteric inhibitors with novel scaffolds for the treatment of patients with KRAS mutation-positive colorectal cancer. |
| Databáze: | OpenAIRE |
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