SHP099 is a highly potent and selective SHP2 inhibitor that can be administered orally, exhibiting an IC50 of 70 nM. The X-ray co-crystal structure of SHP099 bound to SHP2 unveils a novel interaction between the basic amine and the Phe113 backbone carbonyl. SHP099 demonstrates an ability to inhibit cell proliferation in the KYSE-520 model with an IC50 of 1.4 μM. Additionally, SHP099 is characterized by its high solubility and permeability, without significant efflux in Caco-2 cells[1]. SHP099 simultaneously interacts with the interfaces of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thereby allosterically inhibiting SHP2 activity. It also impedes RAS–ERK signaling, which is crucial in halting the proliferation of human cancer cells driven by receptor tyrosine kinases[2].
SHP099 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Mouse spleen T cells
3, 10, or 30 µM
1 hour
To measure the intracellular phosphatase activity of SHP2, results showed that SHP2 activity increased by approximately 40% after treatment with 30 mmol/L oleanolic acid.
Acta Pharm Sin B. 2024 Jun;14(6):2598-2612.
HB11;19
5 µM
1 hour
To study the effect of SHP099 on HB11;19 cells, results showed that the cells developed resistance to SHP099
Cancer Res. 2022 Jun 6;82(11):2141-2155.
MGH049-1A
5 µM
14 days
To evaluate the effect of SHP099 in combination with ceritinib on cell proliferation, results showed that the combination significantly inhibited cell proliferation.
Nat Med. 2018 May;24(4):512-517.
MGH073-2B
5 µM
14 days
To evaluate the effect of SHP099 in combination with ceritinib on cell proliferation, results showed that the combination significantly inhibited cell proliferation.
Nat Med. 2018 May;24(4):512-517.
MGH065-1B
5 µM
14 days
To evaluate the effect of SHP099 in combination with ceritinib on cell proliferation, results showed that the combination significantly inhibited cell proliferation.
Nat Med. 2018 May;24(4):512-517.
MGH045-2A
5 µM
14 days
To evaluate the effect of SHP099 in combination with ceritinib on cell proliferation, results showed that the combination significantly inhibited cell proliferation.
Nat Med. 2018 May;24(4):512-517.
THP-1-derived macrophages
30 µM
2, 4, 6 hours
To investigate the effect of SHP099 on type I interferon signaling in THP-1-derived macrophages, results showed that SHP099 significantly increased the mRNA levels of CXCL10, IFIT1, IFIT2, ISG15 and the expression of IFN-β.
Acta Pharm Sin B. 2022 Jan;12(1):149-166.
BMDMs
500 mg/mL
2, 4, 6 hours
To investigate the effect of SHP2 deletion on type I interferon signaling in BMDMs, results showed that SHP2 deletion significantly increased the mRNA levels of Cxcl10, Ifit1, Ifit2, Isg15 and the expression of IFN-β.
Acta Pharm Sin B. 2022 Jan;12(1):149-166.
RAW264.7 cells
20 µM
24 hours
SHP099 inhibited LPS-induced M1 macrophage polarization, decreased the proportion of CD80+ cells, downregulated M1 macrophage-related inflammatory genes, and reduced the secretion of inflammatory cytokines TNF-α and IL-6.
Acta Pharm Sin B. 2022 Jul;12(7):3073-3084.
Bone marrow-derived macrophages (BMDMs)
20 µM
24 hours
SHP099 inhibited LPS-induced M1 macrophage polarization, decreased the proportion of CD80+ cells, downregulated M1 macrophage-related inflammatory genes, and reduced the secretion of inflammatory cytokines TNF-α and IL-6.
Acta Pharm Sin B. 2022 Jul;12(7):3073-3084.
Murine splenic CD8+ T cells
10 µM
24 hours
To evaluate the effect of SHP099 on the activation of CD8+ T cells, results showed that SHP099 significantly enhanced the production of GZMB and PRF in CD8+ T cells at a concentration of 10 μmol/L.
Acta Pharm Sin B. 2019 Mar;9(2):304-315.
Human peripheral blood mononuclear cells (PBMCs)
10 µM
24 hours
To evaluate the effect of SHP099 on human PBMCs, results showed that SHP099 significantly upregulated the mRNA levels of IFN-γ, GZMB, and PRF.
Acta Pharm Sin B. 2019 Mar;9(2):304-315.
HUVECs
5 µM
24 hours
To investigate the inhibitory effect of SHP099 on HUVECs, the results showed that SHP099 reversed the pro-proliferative effect of E2-treated endothelial cells on endometrial organoids.
Adv Sci (Weinh). 2024 Nov;11(41):e2403038.
KRAS amplified gastric cancer cells
3, 5 or 10 µM
5 days
To evaluate the anti-proliferative effect of SHP099 in combination with GSK1120212 on KRAS amplified gastric cancer cells, results showed significant inhibition of cell proliferation
Nat Med. 2018 Jul;24(7):968-977.
H358 NSCLC cells
10 µM
7 days
To evaluate the effect of SHP099 in combination with MEK inhibitors on colony formation, results showed that cells expressing SHP099-resistant mutants did not respond to the combination treatment
Cancer Discov. 2018 Oct;8(10):1237-1249.
PDAC cell lines
10 µM
7 or 10 days
To evaluate the effect of SHP099 in combination with MEK inhibitors on cell proliferation and colony formation, results showed that the combination significantly inhibited cell proliferation and colony formation
Cancer Discov. 2018 Oct;8(10):1237-1249.
Kmt2d KO LUSC cells
0.559 µM, 0.310 µM, 1.165 µM (IC50)
72 hours
Evaluate the effect of SHP099 on the viability of Kmt2d KO LUSC cells, showing that these cells are highly sensitive to SHP099.
Cancer Cell. 2023 Jan 9;41(1):88-105.e8.
KP cells
10 µM
72 hours
SHP099 significantly inhibited the MEK/ERK signaling pathway in KP cells and induced CXCL1 and CXCL5 expression.
Cancer Discov. 2022 Jan;12(1):47-61.
H1975 cells
10 µM
72 hours
SHP099 significantly inhibited the MEK/ERK signaling pathway in H1975 cells and induced GRO family gene expression.
Cancer Discov. 2022 Jan;12(1):47-61.
Neural progenitor cells (NPCs)
0.1 to 100 µM
72 hours
To evaluate the effects of SHP099 on the survival of neural progenitor cells, it was found that SHP099 significantly inhibited the survival of neural progenitor cells.
Neuro Oncol. 2019 Nov 4;21(11):1423-1435.
GBM cell lines
0.1 to 100 µM
72 hours
To evaluate the effects of SHP099 on the survival of GBM cell lines, it was found that SHP099 significantly inhibited the survival of GBM cell lines.
Neuro Oncol. 2019 Nov 4;21(11):1423-1435.
Patient-derived glioma stem-like cells (GSCs)
0.1 to 100 µM
72 hours
To evaluate the effects of SHP099 on the survival of patient-derived glioma stem-like cells, it was found that SHP099 significantly inhibited the survival of these cells.
Neuro Oncol. 2019 Nov 4;21(11):1423-1435.
MV-4-11
2.5 µM
72 hours
To study the inhibitory effect of SHP099 on MV-4-11 cells, results showed that the cells developed resistance to SHP099
Cancer Res. 2022 Jun 6;82(11):2141-2155.
MOLM-13
10 µM
72 hours
To study the inhibitory effect of SHP099 on MOLM-13 cells, results showed that the cells developed resistance to SHP099
Cancer Res. 2022 Jun 6;82(11):2141-2155.
Alveolar macrophages
10-50 µM
To evaluate the effect of SHP099 on TBET ubiquitination in alveolar macrophages, results showed that 50 μM SHP099 significantly enhanced TBET ubiquitination levels.
Sci Transl Med. 2023 Sep 13;15(713):eade2581.
CT-26 cells
0.3 – 10 µM
To evaluate the effect of SHP099 on the viability of CT-26 cells, results showed that SHP099 did not significantly inhibit the viability of CT-26 cells at concentrations ranging from 0.3 – 10 μmol/L.
Acta Pharm Sin B. 2019 Mar;9(2):304-315.
Lin-negative bone marrow cells
0.1 µM
36~48 hours
SHP099 treatment of Tet2-KO Lin-negative bone marrow cells inhibits IL-6 induced cell survival
Cell Stem Cell. 2018 Dec 6;23(6):833-849.e5.
NCI-H1792
10 μmol/L
48 hours
Evaluate the effect of TNO155 in combination with KRASG12Ci1 on NCI-H1792 cell proliferation, showing high FGFR dependence.
Cancer Res. 2023 Dec 15;83(24):4130-4141.
NCI-H23
10 μmol/L
48 hours
Evaluate the effect of TNO155 in combination with KRASG12Ci1 on NCI-H23 cell proliferation, showing FGFR1 inactivation as the strongest sensitizer.
Cancer Res. 2023 Dec 15;83(24):4130-4141.
SHP099 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Endometrial hyperplasia model
Subcutaneous injection
10 mg/kg
Once daily for 21 days
To investigate the inhibitory effect of SHP099 on endometrial hyperplasia in mice, the results showed that SHP099 significantly alleviated E2-induced endometrial hyperplasia.
Adv Sci (Weinh). 2024 Nov;11(41):e2403038.
129Sv/Ev mice
Anti-PD-1 resistant 344SQ NSCLC adenocarcinoma model
Oral
100 mg/kg
Starting from day 5, continued for 5 days on and 2 days off, until death
To evaluate the effect of SHP099 combined with radiotherapy and anti-PD-L1, results showed that the combination therapy significantly enhanced local and abscopal tumor control, reduced lung metastases, and improved mouse survival.
Cancer Immunol Res. 2020 Jul;8(7):883-894.
C57BL/6J mice
Orthotopic xenograft models
Oral gavage
100 mg/kg
Single dose, observed for 24 hours
To evaluate the pharmacokinetics of SHP099 in vivo and its antitumor effects on orthotopic xenograft models of glioblastoma, it was found that SHP099 reached effective concentrations in brain tissues and significantly inhibited tumor growth.
Neuro Oncol. 2019 Nov 4;21(11):1423-1435.
Mice
Inv(16)/ KitD816Y AML model
100 nmol/L
10 days
To study the effect of RMC-4550 on the inv(16)/ KitD816Y AML mouse model, results showed that combined treatment with RMC-4550 and BLU-285 significantly reduced AML clonogenic potential
Cancer Res. 2022 Jun 6;82(11):2141-2155.
C57BL/6 mice
Destabilization of medial meniscus (DMM)-induced osteoarthritis model
Intra-articular injection
20 µmol/L
Twice a week for two weeks
SHP099 significantly attenuated DMM-induced osteoarthritis progression by inhibiting M1 macrophage polarization, including joint synovitis and cartilage damage.
Acta Pharm Sin B. 2022 Jul;12(7):3073-3084.
C57BL/6 mice
MC38 colon cancer xenograft model
Oral
5 mg/kg
Once daily for 14 days
To evaluate the anti-tumor effect of SHP099 in the MC38 colon cancer xenograft model, results showed that SHP099 significantly reduced tumor volume and weight, and enhanced anti-tumor immune responses in the tumor microenvironment.
Acta Pharm Sin B. 2022 Jan;12(1):149-166.
Mice
TNBS-induced colitis model
Oral or intraperitoneal injection
5 mg/kg
Daily administration for 4 days
To verify whether the improvement of TNBS-induced colitis by oleanolic acid was dependent on SHP2, results showed that SHP099 eliminated the ameliorative effect of oleanolic acid.
Acta Pharm Sin B. 2024 Jun;14(6):2598-2612.
BALB/c mice
CT-26 colon cancer xenograft model
Intraperitoneal injection
5 mg/kg
Once daily, until the end of the experiment
To evaluate the effect of SHP099 on tumor growth in the CT-26 colon cancer xenograft model, results showed that SHP099 significantly reduced tumor volume and weight without affecting the overall health of the mice.
Acta Pharm Sin B. 2019 Mar;9(2):304-315.
NOD-SCID mice
KRAS amplified gastric cancer xenograft model
Oral
50 mg/kg
Daily for 5 weeks
To evaluate the anti-tumor effect of SHP099 in combination with GSK1120212 on KRAS amplified gastric cancer xenograft models, results showed significant inhibition of tumor growth
Nat Med. 2018 Jul;24(7):968-977.
Mice
KP NSCLC allograft model
Oral gavage
75 mg/kg
Once daily for 4 weeks
SHP099 significantly inhibited KP tumor growth, increased T-cell infiltration, but also increased granulocytic myeloid-derived suppressor cell (gMDSC) infiltration.
Cancer Discov. 2022 Jan;12(1):47-61.
Nu/Nu mice
Subcutaneous xenograft model
Oral
75 mg/kg SHP099, 25 mg/kg ceritinib
Daily, continuous treatment
To evaluate the effect of SHP099 in combination with ceritinib on tumor growth, results showed that the combination significantly inhibited tumor growth.
Nat Med. 2018 May;24(4):512-517.
Mice
Capan-2, MIAPaCa-2 and H358 xenograft models
Oral
SHP099 75 mg/kg, trametinib 0.25 mg/kg
SHP099 daily, trametinib daily, for 37, 19, or 21 days
To evaluate the effect of SHP099 in combination with MEK inhibitors on tumor growth, results showed that the combination significantly inhibited tumor growth and reduced tumor cellularity and vascularity
Cancer Discov. 2018 Oct;8(10):1237-1249.
Mice
Kmt2d KO LUSC model
Oral
SHP099 75mpk, afatinib 10mpk
Once daily, 5 days/week
Evaluate the effect of SHP099 and afatinib on the growth of Kmt2d KO LUSC tumors, showing that the combination therapy significantly inhibits tumor growth and prolongs survival.
Cancer Cell. 2023 Jan 9;41(1):88-105.e8.
SHP099 动物研究
Animal study
Following administration of a single dose at 30 mg/kg and 100 mg/kg, a dose-responsive relationship is evident in the exposure and modulation of the pharmacodynamic biomarker p-ERK within the xenografts. Administering a daily oral dose of 10 mg/kg or 30 mg/kg results in tumor growth inhibition of 19% and 61%, respectively. Complete tumor stasis is observed with a daily dose of 100 mg/kg[1].
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