PCC0208023, a potent SHP2 allosteric inhibitor, imparts an antitumor effect against KRAS mutant colorectal cancer
Abstract
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.
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Inhibition of the RAS/MAPK signaling pathway was confirmed by the reduction of p-MEK, p-ERK, p-SHP2, and RAS-GTP levels in LS180 and HCT116 cells after PCC0208023 treatment, which also inhibited the proliferation of CRC cell lines.
“Inhibition of the RAS/MAPK signaling pathway was confirmed by the reduction of p-MEK, p-ERK, p-SHP2, and RAS-GTP levels in LS180 and HCT116 cells after PCC0208023 treatment, which also inhibited the proliferation of CRC cell lines.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [292]
PCC0208023 has an IC50 value of 2.10 nM for the SHP2 holoenzyme and lacks activity against the SHP2 free catalytic domain.
“The study demonstrated that PCC0208023 has an IC50 value of 2.10 nM for the SHP2 holoenzyme and lacks activity against the SHP2 free catalytic domain.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [292]
In an in vivo study, PCC0208023 demonstrated antitumor efficacy in a subcutaneous LS180 xenograft model, significantly reducing tumor weight and growth without any significant effect on mouse body weight.
“Furthermore, in an in vivo study, PCC0208023 demonstrated antitumor efficacy in a subcutaneous LS180 xenograft model, significantly reducing tumor weight and growth without any significant effect on mouse body weight.292”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [292]
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- Authors
- Chen, X., Zou, F., Hu, Z., Du, G., Yu, P., Wang, W., Wang, H., Ye, L., & Tian, J.
- Affiliations
- Yantai University (CN)
- Binzhou Medical University (CN)
- Corresponding author
- Ye, Liang
- Tian, Jingwei
- Venue
- Toxicology and Applied Pharmacology
- Publisher
- Elsevier BV
- Published
- 2020-07
- Volume
- 398
- Pages
- 115019
- ISSN
- 0041-008X (ISSN-L)
- OpenAlex
- W3019926577
- Cited by
- 20
- References
- 38
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 7 · 2020: 1
- FWCI
- 1.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Toxicology and Applied Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- SHP2, PTPN11, allosteric inhibitors, KRAS mutation, colorectal cancer, RAS/MAPK pathway, non-competitive inhibition, xenograft models, apoptosis, Ki-67, ERK1/2 phosphorylation, drug distribution, molecular docking
- MeSH terms
- Animals, Antineoplastic Agents, Female, Humans, Mice, Inbred BALB C, Mice, Nude, Mutation, Colorectal Neoplasms, Signal Transduction, Proto-Oncogene Proteins p21(ras), Mitogen-Activated Protein Kinase Kinases, MAP Kinase Signaling System, Xenograft Model Antitumor Assays, HCT116 Cells, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 11
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