Allosteric inhibition of SHP2 by SHP099 also potently enhanced the anti-tumor immunity induced by IFNα by modulating T cell proliferation and infiltration in vitro and in vivo. These results reveal the new function of SHP2 in NLRP3 inflammasome activation and pyroptosis in RCC and provide a basis for further investigating the combination of allosteric SHP2 inhibitors with IFNα in cancer immunotherapy.

P1, N=53, Terminated, Pfizer | Trial completion date: Nov 2025 --> Jun 2024 | Active, not recruiting --> Terminated; The study was prematurely discontinued due to strategic reasons, not major safety concerns, futility, or requests from any regulatory authorities

In an immune excluded model, combined RAS and SHP2 inhibition sensitises tumours to immune checkpoint blockade, leading to efficient tumour immune rejection. These preclinical results demonstrate the potential of the combination of RAS(ON) G12C-selective inhibitors with SHP2 inhibitors to sensitize tumours to immune checkpoint blockade.

P1/2, N=126, Completed, Jacobio Pharmaceuticals Co., Ltd. | Recruiting --> Completed

Notably, flow cytometry, ELISA and immunofluorescence experiments showed that C6 remarkably decreased the population of CD206+/Ly6C+ M2-like tumor-associated macrophages (TAMs), the expression level of interleukin-10 (IL-10), and the number of F4/80+/CD206+ M2-like TAMs, suggesting that C6 could effectively alleviate the activation and infiltration of M2-like TAMs. Taken together, these results illustrate that C6 is a promising SHP2 inhibitor worthy of further development.

P1/2, N=12, Completed, Jacobio Pharmaceuticals Co., Ltd. | Recruiting --> Completed | Phase classification: P1b/2a --> P1/2 | N=118 --> 12 | Trial completion date: Oct 2022 --> Dec 2023 | Trial primary completion date: Feb 2022 --> Dec 2023

Furthermore, targeting SHP2 using SHP099 (an allosteric inhibitor) or endothelial-specific SHP2 deletion alleviates endothelial cell activation, macrophage infiltration, and EH progression in mice. Collectively, the findings demonstrate that SHP2 mediates the transition of endothelial activation from estradiol-driven acute inflammation to macrophage-amplified chronic inflammation. Targeting sterile inflammation mediated by endothelial cell activation is a promising strategy for nonhormonal intervention in estrogen-related diseases.

P3, N=392, Recruiting, Jacobio Pharmaceuticals Co., Ltd. | Not yet recruiting --> Recruiting

19F MRI might provide non-invasive longitudinal estimates for abundance and spatial distribution of CD11b+ macrophages/monocytes in pancreatic cancer.

P1, N=172, Active, not recruiting, Genentech, Inc. | Recruiting --> Active, not recruiting

P1, N=200, Active, not recruiting, Erasca, Inc. | Trial completion date: May 2024 --> Jul 2025 | Trial primary completion date: May 2024 --> May 2025

P1/2, N=200, Active, not recruiting, Erasca, Inc. | Phase classification: P1b/2 --> P1/2 | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: May 2024 --> May 2025

In this study, we demonstrated that MEST inhibited IFN-γ secretion from CD8+ T cells by up-regulating SHP2, thereby downregulating MHCI expression in GC cells to promote immune escape and providing a new T cell-based therapeutic potential for GC.

JAB-3312 was well-tolerated in animal models, and a close correlation was observed between the plasma concentration of JAB-3312 and the p-ERK inhibition in tumors. Currently, JAB-3312 is undergoing clinical trials as a potential anticancer agent.

P2, N=72, Recruiting, Suzhou Genhouse Bio Co., Ltd. | Not yet recruiting --> Recruiting

To counteract the elevated RAS-MAPK signaling in both NF1-deficient Schwann cells and SSPCs, we used MAPK kinase (MEK) and Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) inhibitors. Combined MEK-SHP2 inhibition in vivo prevented fibrous nonunion in the Prss56-Nf1 knockout mouse model, providing a promising therapeutic strategy for the treatment of fibrous nonunion in CPT.

P1, N=4, Terminated, LianBio LLC | Phase classification: P1a/1b --> P1 | N=52 --> 4 | Trial completion date: Jul 2026 --> Mar 2024 | Recruiting --> Terminated | Trial primary completion date: Dec 2025 --> Mar 2024; Business reason

P1, N=7, Terminated, LianBio LLC | N=28 --> 7 | Trial completion date: Sep 2024 --> Mar 2024 | Recruiting --> Terminated; Business reason

Here, a TAMs-targeted albumin nanoparticles-based delivery system (M@SINPs) was constructed for the co-delivery of photosensitizer IR820 and SHP2 inhibitor SHP099 to potentiate macrophage-mediated cancer immunotherapy...Furthermore, M@SINPs in combination with anti-PD-1 antibody could also improve the treatment outcomes of PD-1 blockade and exert the synergistic anticancer effects. Thus, the macrophage repolarization/phagocytosis restoration combination through M@SINPs holds promise as a strategy to concurrently remodel TAMs in TME for improving the antitumor efficiency of immune checkpoint block and conventional therapy.

P1, N=227, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting

P1/2, N=5, Terminated, Bristol-Myers Squibb | N=410 --> 5 | Active, not recruiting --> Terminated; Business objectives have changed

An overview of claimed structures is conducted, focusing attention on structural modifications compared to SHP099, the first described allosteric inhibitor of SHP2...Until now, long-term benefit of SHP2 inhibitors as monotherapy agents have not been demonstrated due to acquired mechanisms of resistance and/or lack of efficacy. However, combination therapies with a variety of agents, such as MEK, BRAF, EGFR, RAS-G12C and PDL-1 inhibitors, have high potential and are currently an extensive area of investigation.

P1/2, N=126, Not yet recruiting, Suzhou Genhouse Bio Co., Ltd.

P3, N=392, Not yet recruiting, Jacobio Pharmaceuticals Co., Ltd.

P1/2, N=65, Terminated, Sanofi | Active, not recruiting --> Terminated; Sponsor's decision not related to any safety concern

Besides, we proved that cisplatin could activate SHP2 and SHP099 increased sensitivity to cisplatin in GC. Taken together, our results provide evidence that the SHP2/PKM2/AMPK axis exerts a key role in GC progression and glycolysis and could be a viable therapeutic approach for the therapy of GC.

P1, N=53, Active, not recruiting, Pfizer | N=36 --> 53

P1/2, N=410, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting | Trial completion date: Jul 2029 --> May 2024 | Trial primary completion date: Aug 2027 --> May 2024

P1, N=68, Recruiting, Suzhou Genhouse Bio Co., Ltd. | Not yet recruiting --> Recruiting | Trial primary completion date: Feb 2024 --> Dec 2024

P2, N=72, Not yet recruiting, Suzhou Genhouse Bio Co., Ltd.

P1, N=130, Active, not recruiting, Navire Pharma Inc., a BridgeBio company | Recruiting --> Active, not recruiting

P1/2, N=94, Recruiting, Suzhou Genhouse Bio Co., Ltd.

At days 8 and 15, respectively, 310 and 42 significant differentially expressed genes were identified between groups (false discovery rate adjusted p1). SFX-01 treatment did not improve clinical status or modulate key Nrf2 targets in patients with CAP primarily due to SARS-CoV-2 infection.

P1, N=0, Withdrawn, Novartis Pharmaceuticals | N=48 --> 0 | Trial completion date: Jun 2024 --> Jul 2025 | Not yet recruiting --> Withdrawn | Trial primary completion date: Jun 2024 --> Jul 2025

P1, N=0, Withdrawn, Novartis Pharmaceuticals | N=48 --> 0 | Trial completion date: Jun 2024 --> Jun 2025 | Not yet recruiting --> Withdrawn | Trial primary completion date: Jun 2024 --> Jun 2025

The combination of the HDAC inhibitor SAHA and SHP2 inhibitor SHP099 suppressed the progression of lung cancer markedly in vitro and in vivo. Therefore, we revealed the epigenetic silencing mechanism of PTPRR and demonstrated that combination therapy targeting HDAC and SHP2 might represent a novel strategy to treat RAS-mutant lung cancer.

P2, N=20, Ongoing, Jacobio Pharmaceuticals Co., Ltd.

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...Furthermore, the combination therapy of compound 4b and KRAS inhibitor sotorasib would play a strong synergistic effect against 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.

NanoSHP099 is identified to be simultaneously enriched in tumor and thrombus foci, exerting dual tumor-suppression and thrombolysis effects. NanoSHP099 presents a superior thrombus dissolution effect than that of the same dosage of SHP099 because of the higher Ly6C monocyte/macrophage proportion and MMP2/MMP9 collagenolytic activities in organized thrombi.

P1, N=122, Terminated, Novartis Pharmaceuticals | Active, not recruiting --> Terminated; Business reasons

P1/2, N=65, Active, not recruiting, Sanofi | Trial completion date: Jul 2024 --> Mar 2024 | Trial primary completion date: Jul 2024 --> Mar 2024

P1, N=255, Recruiting, Novartis Pharmaceuticals | Trial completion date: Oct 2024 --> Apr 2025 | Trial primary completion date: Oct 2024 --> Apr 2025